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de Borst MH. Fibroblast growth factor 23 as a risk factor for incident diabetes. Curr Opin Nephrol Hypertens 2025; 34:284-290. [PMID: 40237064 DOI: 10.1097/mnh.0000000000001078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
PURPOSE OF REVIEW Diabetes is a major global health concern, affecting millions and increasing morbidity and mortality. Recent research highlights fibroblast growth factor 23 (FGF23) as a potential contributor to type 2 diabetes and its cardiovascular complications. This review explores the role of FGF23 in metabolic and cardiovascular dysfunction and discusses possible therapeutic interventions. RECENT FINDINGS Deregulated FGF23 is linked to insulin resistance, pancreatic β-cell dysfunction, and systemic inflammation. Studies suggest FGF23 influences glucose metabolism via insulin signaling, oxidative stress, and inflammation. Epidemiological data indicate that elevated FGF23 levels are associated with an increased risk of type 2 diabetes and posttransplant diabetes, independent of traditional risk factors. Higher FGF23 levels have also been linked with an increased cardiovascular risk in patients with diabetes, even without chronic kidney disease. SUMMARY FGF23 is emerging as a key factor in the cardiovascular-kidney-metabolic syndrome, connecting diabetes and cardiovascular disease. While studies suggest consistent associations, causal mechanisms remain unclear. No therapies specifically target FGF23 to lower diabetes risk, but fibroblast growth factor receptor 4 (FGFR4) inhibitors show promise. Future research should examine the role of FGF23 in individuals with normal kidney function and explore whether modifying its levels could reduce diabetes and cardiovascular risk.
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Affiliation(s)
- Martin H de Borst
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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2
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Persiani E, Ceccherini E, Falleni A, Gisone I, Ippolito C, Mattii L, Cecchettini A, Vozzi F. Ultrastructural and Molecular Analysis of Vascular Smooth Muscle Cells During the Switch from a Physiological to a Pathological Phenotype. Biomedicines 2025; 13:1127. [PMID: 40426954 PMCID: PMC12108999 DOI: 10.3390/biomedicines13051127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/23/2025] [Accepted: 04/25/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: Under physiological conditions, vascular smooth muscle cells (VSMCs) are in a quiescent contractile state, but under pathological conditions, such as atherosclerosis, they change their phenotype to synthetic, characterized by increased proliferation, migration, and production of an extracellular matrix. Furthermore, VSMCs can undergo calcification, switching to an osteoblast-like phenotype, contributing to plaque instability. Methods: In this study, we analyzed the phenotypic changes in VSMCs during the transition from a physiological to a pathological state, a key process in the progression of atherosclerosis, using confocal and transmission electron microscopy, real-time PCR, and intracellular calcium quantification. Results: Confocal and transmission electron microscopy revealed a prominent remodeling of the actin cytoskeleton, increasing autophagic vacuoles in synthetic VSMCs and the deposition of calcium microcrystals in calcified cells. Immunofluorescence analysis revealed differential expression of α-SMA (contractile marker) and galectin-3 (synthetic marker), confirming the phenotypic changes. Real-time PCR further validated these changes, showing upregulation of RUNX-2, a marker of osteogenic transition, in calcified VSMCs. Conclusions: This study highlights the dynamic plasticity of VSMCs and their role in atherosclerosis progression. Understanding the characteristics of these phenotypic transitions can help develop targeted therapies to mitigate vascular calcification and plaque instability, potentially countering cardiovascular disease.
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Affiliation(s)
- Elisa Persiani
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.P.); (I.G.); (A.C.); (F.V.)
| | - Elisa Ceccherini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.P.); (I.G.); (A.C.); (F.V.)
| | - Alessandra Falleni
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (A.F.); (C.I.); (L.M.)
| | - Ilaria Gisone
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.P.); (I.G.); (A.C.); (F.V.)
| | - Chiara Ippolito
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (A.F.); (C.I.); (L.M.)
| | - Letizia Mattii
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (A.F.); (C.I.); (L.M.)
| | - Antonella Cecchettini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.P.); (I.G.); (A.C.); (F.V.)
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (A.F.); (C.I.); (L.M.)
| | - Federico Vozzi
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (E.P.); (I.G.); (A.C.); (F.V.)
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Cai Z, Xu S, Xiao X, Liu C, Zu L. Mib2 Regulates Lipid Metabolism in Heart Failure With Preserved Ejection Fraction via the Runx2-Hmgcs2 Axis. J Cell Mol Med 2025; 29:e70514. [PMID: 40159625 PMCID: PMC11955417 DOI: 10.1111/jcmm.70514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/18/2025] [Accepted: 03/14/2025] [Indexed: 04/02/2025] Open
Abstract
Obesity and the mismanagement of lipids significantly contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, the underlying molecular mechanisms that regulate the metabolic changes and disruptions in lipid balance within HFpEF remain to be fully understood. Transcriptome data for HFpEF were sourced from the National Center for Biotechnology Information (NCBI) database. A mouse model for HFpEF was developed utilising leptin-deficient (ob/ob) mice. The cardiac-specific mind bomb E3 ubiquitin protein ligase 2 (Mib2) overexpression in ob/ob mice was achieved by tail vein injection of a recombinant adeno-associated virus serotype 9 vector carrying Mib2 with a cTNT promoter (AAV9-cTNT-Mib2). In vitro, neonatal rat ventricular myocytes were exposed to fatty acid to induce lipotoxicity. The molecular mechanisms were investigated through proteomic analysis, dual luciferase reporter gene assay, and immunoprecipitation assays. GO and KEGG enrichment analyses indicated that the differentially expressed proteins (DEPs) in HFpEF were prominently enriched in pathways related to the fatty acid metabolic process. The transcriptomic and proteomic analyses of heart tissues from HFpEF mice presented a notable elevation in the expression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2). Immunoprecipitation assays revealed that mind bomb 2 (Mib2) directly interacted with runt-related transcription factor 2 (Runx2), ubiquitinating and degrading Runx2 to inhibit Hmgcs2 transcription, impeding the fatty acid metabolic process. Mice with cardiac-specific overexpression of Mib2 displayed a more pronounced progression of cardiac dysfunction and an accumulation of lipids compared to the control group. Our research uncovers a mechanism by which Mib2 modulates cardiac lipid metabolic homeostasis in HFpEF, implicating the Runx2-Hmgcs2 axis.
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Affiliation(s)
- Zhulan Cai
- Department of Cardiology and Institute of Vascular MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijingChina
- NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesPeking UniversityBeijingChina
- Beijing Key Laboratory of Cardiovascular Receptors ResearchBeijingChina
| | - Shunyao Xu
- Department of Critical Care MedicineShenzhen People's Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and TechnologyShenzhenChina
| | - Xiaohua Xiao
- Department of GeriatricsThe First Affiliated Hospital of Shenzhen University, Shenzhen Second People's HospitalShenzhenChina
| | - Chen Liu
- Department of GeriatricsThe First Affiliated Hospital of Shenzhen University, Shenzhen Second People's HospitalShenzhenChina
| | - Lingyun Zu
- Department of Cardiology and Institute of Vascular MedicinePeking University Third HospitalBeijingChina
- State Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijingChina
- NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory PeptidesPeking UniversityBeijingChina
- Beijing Key Laboratory of Cardiovascular Receptors ResearchBeijingChina
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Luo J, Wang Q, Liu W, Liao H, Qing W, Zhang M, Tang D, Luo G, Zhao H. Computed tomography provides a "one-stop-shop" targeted analysis for coronary artery calcification and osteoporosis: a review. Front Endocrinol (Lausanne) 2025; 16:1356831. [PMID: 40093749 PMCID: PMC11906312 DOI: 10.3389/fendo.2025.1356831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 02/05/2025] [Indexed: 03/19/2025] Open
Abstract
The global trend towards longer lifespans has led to an aging population and a rise in the prevalence of diseases that predominantly affect elderly people. Coronary artery calcification (CAC) and osteoporosis (OP) are common in elderly populations. CT scans provide a reliable method to assess and monitor the progression of these diseases. In this review, the relationship between OP and CAC in terms of pathophysiological mechanism, comorbidity risk factors and clinical manifestations is reviewed, with a focus on the advancements in CT imaging, clinical applications and the possibility for "one-stop-shop" for examination.
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Affiliation(s)
- Jing Luo
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Qian Wang
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
- Department of Radiology, Hong’an County People’s Hospital, Huanggang, Hubei, China
| | - Wenhong Liu
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Huazhi Liao
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Weipeng Qing
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Minyi Zhang
- Major in Medical Imaging, The University of South China, Hengyang, Hunan, China
| | - Deqiu Tang
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Guanghua Luo
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
| | - Heng Zhao
- Department of Radiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China
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Niu H, Liu Z, Guan Y, Wen J, Dang Y, Guan J. Harnessing synergistic effects of MMP-2 Inhibition and bFGF to simultaneously preserve and vascularize cardiac extracellular matrix after myocardial infarction. Acta Biomater 2025; 191:189-204. [PMID: 39532649 DOI: 10.1016/j.actbio.2024.10.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/15/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Myocardial infarction (MI) leads to cardiac extracellular matrix (ECM) degradation and fibrosis, reducing heart function. Consequently, simultaneously addressing ECM degradation and inhibiting cardiac fibrosis is essential for preserving heart function and mitigating adverse remodeling. However, the preserved ECM becomes unstable if not vascularized, as its structure and composition undergo changes over time. ECM vascularization is crucial to improve cardiac function. Presently, there is no clinically approved therapy that can simultaneously preserve and vascularize the ECM, and inhibit cardiac fibrosis. Our study develops a drug delivery system aiming to achieve these goals. It includes the peptide CTTHWGFTLC (CTT), a specific MMP-2 inhibitor, and basic fibroblast growth factor (bFGF), a potent factor with pro-angiogenic and anti-fibrotic properties. An injectable hydrogel serves as the carrier, featuring a rapid gelation that allows for the substantial retention of drugs. Additionally, the hydrogel has the capability to scavenge upregulated reactive oxygen species (ROS), thereby reducing tissue inflammation. Our findings indicate that CTT and bFGF synergistically enhance endothelial cell migration and tube formation while inhibiting the differentiation of fibroblasts into myofibroblasts. Upon delivery into hearts, the system significantly decreases MMP-2 level, promotes angiogenesis, attenuates cardiac fibrosis, and alleviates inflammation, resulting in a noteworthy cardiac function improvement. STATEMENT OF SIGNIFICANCE: 1) This work addresses key challenges in cardiac repair after myocardial infarction (MI), including extracellular matrix (ECM) degradation, vascularization, and fibrosis. 2) We combined an MMP-2/9 inhibitor (CTT) with bFGF to prevent ECM degradation, enhance vascularization, and inhibit fibrosis, providing a comprehensive strategy to improve cardiac function. 3) An injectable hydrogel was developed with rapid gelation and mechanical properties similar to heart tissue, ensuring efficient drug retention and reducing tissue stress. 4) The hydrogel enabled controlled, spatiotemporal release of CTT to dynamically reduce MMP-2/9 activity, and gradually released bFGF to promote angiogenesis and inhibit fibrosis.
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Affiliation(s)
- Hong Niu
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Center of Regenerative Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA
| | - Zhongting Liu
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Ya Guan
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Jiaxing Wen
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Yu Dang
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Jianjun Guan
- Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, USA; Center of Regenerative Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA; Institute of Materials Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA.
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Afsar B, Afsar RE, Caliskan Y, Lentine KL. The Relationship between Sclerostin and Kidney Transplantation Mineral Bone Disorders: A Molecule of Controversies. Calcif Tissue Int 2024; 115:339-361. [PMID: 39078512 PMCID: PMC11405501 DOI: 10.1007/s00223-024-01261-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 07/06/2024] [Indexed: 07/31/2024]
Abstract
Kidney transplantation is the most effective treatment option for most patients with end-stage kidney disease due to reduced mortality, decreased cardiovascular events and increased quality of life compared to patients treated with dialysis. However, kidney transplantation is not devoid of both acute and chronic complications including mineral bone disorders (MBD) which are already present in patients with chronic kidney disease (CKD) before kidney transplantation. The natural history of MBD after kidney transplantation is variable and new markers are needed to define MBD after kidney transplantation. One of these promising molecules is sclerostin. The main action of sclerostin is to inhibit bone formation and mineralization by blocking osteoblast differentiation and function. In kidney transplant recipients (KTRs), various studies have shown that sclerostin is associated with graft function, bone parameters, vascular calcification, and arterial stiffness although non-uniformly. Furthermore, data for inhibition of sclerostin with monoclonal antibody romosozumab for treatment of osteoporosis is available for general population but not in KTRs which osteoporosis is highly prevalent. In this narrative review, we have summarized the studies investigating the change of sclerostin before and after kidney transplantation, the relationship between sclerostin and laboratory parameters, bone metabolism and vascular calcification in the context of kidney transplantation. We also pointed out the uncertainties, explained the causes of divergent findings and suggest further potential study topics regarding sclerostin in kidney transplantation.
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Affiliation(s)
- Baris Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey.
- Department of Nephrology, Saint Loui University, Saint Louis University Hospital, Saint Louis, MO, USA.
| | - Rengin Elsurer Afsar
- Department of Nephrology, School of Medicine, Suleyman Demirel University, Isparta, Turkey
- Department of Nephrology, Saint Loui University, Saint Louis University Hospital, Saint Louis, MO, USA
| | - Yasar Caliskan
- Department of Nephrology, Saint Loui University, Saint Louis University Hospital, Saint Louis, MO, USA
| | - Krista L Lentine
- Department of Nephrology, Saint Loui University, Saint Louis University Hospital, Saint Louis, MO, USA
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7
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Ortega MA, Pekarek T, De Leon-Oliva D, Boaru DL, Fraile-Martinez O, García-Montero C, Bujan J, Pekarek L, Barrena-Blázquez S, Gragera R, Rodríguez-Benitez P, Hernández-Fernández M, López-González L, Díaz-Pedrero R, Asúnsolo Á, Álvarez-Mon M, García-Honduvilla N, Saez MA, De León-Luis JA, Bravo C. Placental Tissue Calcification and Its Molecular Pathways in Female Patients with Late-Onset Preeclampsia. Biomolecules 2024; 14:1237. [PMID: 39456171 PMCID: PMC11506500 DOI: 10.3390/biom14101237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 08/20/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
Preeclampsia (PE) is a complex multisystem disease characterized by hypertension of sudden onset (>20 weeks' gestation) coupled with the presence of at least one additional complication, such as proteinuria, maternal organ dysfunction, or uteroplacental dysfunction. Hypertensive states during pregnancy carry life-threatening risks for both mother and baby. The pathogenesis of PE develops due to a dysfunctional placenta with aberrant architecture that releases factors contributing to endothelial dysfunction, an antiangiogenic state, increased oxidative stress, and maternal inflammatory responses. Previous studies have shown a correlation between grade 3 placental calcifications and an elevated risk of developing PE at term. However, little is known about the molecular pathways leading to placental calcification. In this work, we studied the gene and protein expression of c-Jun N-terminal kinase (JNK), Runt-related transcription factor 2 (RUNX2), osteocalcin (OSC), osteopontin (OSP), pigment epithelium-derived factor (PEDF), MSX-2/HOX8, SOX-9, WNT-1, and β-catenin in placental tissue from women with late-onset PE (LO-PE). In addition, we employed von Kossa staining to detect mineral deposits in placental tissues. Our results show a significant increase of all these components in placentas from women with LO-PE. Therefore, our study suggests that LO-PE may be associated with the activation of molecular pathways of placental calcification. These results could be the starting point for future research to describe the molecular mechanisms that promote placental calcification in PE and the development of therapeutic strategies directed against it.
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Affiliation(s)
- Miguel A. Ortega
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Tatiana Pekarek
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Diego De Leon-Oliva
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Julia Bujan
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Leonel Pekarek
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Silvestra Barrena-Blázquez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
- Department of Nursing and Physiotherapy, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Raquel Gragera
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
| | - Patrocinio Rodríguez-Benitez
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (P.R.-B.); (J.A.D.L.-L.); (C.B.)
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
- Department of Nephrology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
| | - Mauricio Hernández-Fernández
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Laura López-González
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Raul Díaz-Pedrero
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Ángel Asúnsolo
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain;
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
- Immune System Diseases-Rheumatology and Internal Medicine Service, University Hospital Prince of Asturias, Networking Research Center on for Liver and Digestive Diseases (CIBEREHD), 28806 Alcala de Henares, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
| | - Miguel A. Saez
- Department of Medicine and Medical Specialities, (CIBEREHD), Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain; (T.P.); (D.D.L.-O.); (D.L.B.); (O.F.-M.); (C.G.-M.); (J.B.); (L.P.); (R.G.); (M.Á.-M.); (N.G.-H.); (M.A.S.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain; (S.B.-B.); (L.L.-G.); (R.D.-P.); (Á.A.)
- Pathological Anatomy Service, University Hospital Gómez-Ulla, 28806 Alcala de Henares, Spain
| | - Juan A. De León-Luis
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (P.R.-B.); (J.A.D.L.-L.); (C.B.)
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Coral Bravo
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain; (P.R.-B.); (J.A.D.L.-L.); (C.B.)
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
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8
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Liang X, Li Y, Wang P, Liu H. Key regulators of vascular calcification in chronic kidney disease: Hyperphosphatemia, BMP2, and RUNX2. PeerJ 2024; 12:e18063. [PMID: 39308809 PMCID: PMC11416758 DOI: 10.7717/peerj.18063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 08/19/2024] [Indexed: 09/25/2024] Open
Abstract
Vascular calcification is quite common in patients with end-stage chronic kidney disease and is a major trigger for cardiovascular complications in these patients. These complications significantly impact the survival rate and long-term prognosis of individuals with chronic kidney disease. Numerous studies have demonstrated that the development of vascular calcification involves various pathophysiological mechanisms, with the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) being of utmost importance. High phosphate levels, bone morphogenetic protein 2 (BMP2), and runt-related transcription factor 2 (RUNX2) play crucial roles in the osteogenic transdifferentiation process of VSMCs. This article primarily reviews the molecular mechanisms by which high phosphate, BMP2, and RUNX2 regulate vascular calcification secondary to chronic kidney disease, and discusses the complex interactions among these factors and their impact on the progression of vascular calcification. The insights provided here aim to offer new perspectives for future research on the phenotypic switching and osteogenic transdifferentiation of VSMCs, as well as to aid in optimizing clinical treatment strategies for this condition, bearing significant clinical and scientific implications.
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Affiliation(s)
- Xinhua Liang
- Affiliated Hospital of Guangdong Medical University, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Zhanjiang, Guangdong Province, China
| | - Yankun Li
- Affiliated Hospital of Guangdong Medical University, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Zhanjiang, Guangdong Province, China
| | - Peng Wang
- Affiliated Hospital of Guangdong Medical University, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Zhanjiang, Guangdong, China
| | - Huafeng Liu
- Affiliated Hospital of Guangdong Medical University, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Zhanjiang, Guangdong, China
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9
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Jia K, Luo X, Yi J, Zhang C. Hormonal influence: unraveling the impact of sex hormones on vascular smooth muscle cells. Biol Res 2024; 57:61. [PMID: 39227995 PMCID: PMC11373308 DOI: 10.1186/s40659-024-00542-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/26/2024] [Indexed: 09/05/2024] Open
Abstract
Sex hormones play a pivotal role as endocrine hormones that exert profound effects on the biological characteristics and vascular function of vascular smooth muscle cells (VSMCs). By modulating intracellular signaling pathways, activating nuclear receptors, and regulating gene expression, sex hormones intricately influence the morphology, function, and physiological state of VSMCs, thereby impacting the biological properties of vascular contraction, relaxation, and growth. Increasing evidence suggests that abnormal phenotypic changes in VSMCs contribute to the initiation of vascular diseases, including atherosclerosis. Therefore, understanding the factors governing phenotypic alterations in VSMCs and elucidating the underlying mechanisms can provide crucial insights for refining interventions targeted at vascular diseases. Additionally, the varying levels of different types of sex hormones in the human body, influenced by sex and age, may also affect the phenotypic conversion of VSMCs. This review aims to explore the influence of sex hormones on the phenotypic switching of VSMCs and the development of associated vascular diseases in the human body.
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Affiliation(s)
- Keran Jia
- Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Xin Luo
- Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Jingyan Yi
- Department of Medical Cell Biology and Genetics, School of Basic Medical Sciences, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China.
| | - Chunxiang Zhang
- Department of Cardiology, The Affiliated Hospital, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou, Sichuan, 646000, China.
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10
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Zhai X, Cao S, Wang J, Qiao B, Liu X, Hua R, Zhao M, Sun S, Han Y, Wu S, Pang J, Yuan Q, Wang B, Xu F, Wei S, Chen Y. Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification. Circulation 2024; 149:1752-1769. [PMID: 38348663 DOI: 10.1161/circulationaha.123.065830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 01/19/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing β-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.
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MESH Headings
- Animals
- Aldehydes/metabolism
- Vascular Calcification/metabolism
- Vascular Calcification/genetics
- Vascular Calcification/pathology
- Humans
- Core Binding Factor Alpha 1 Subunit/metabolism
- Core Binding Factor Alpha 1 Subunit/genetics
- Aldehyde Dehydrogenase, Mitochondrial/genetics
- Aldehyde Dehydrogenase, Mitochondrial/metabolism
- Mice
- Mice, Knockout
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/drug effects
- Male
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Female
- Middle Aged
- Coronary Artery Disease/metabolism
- Coronary Artery Disease/genetics
- Coronary Artery Disease/pathology
- Cells, Cultured
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/pathology
- Aged
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Affiliation(s)
- Xiaoxuan Zhai
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
| | - Shengchuan Cao
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
| | - Jiali Wang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Bao Qiao
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Xuehao Liu
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Rui Hua
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Menglin Zhao
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Shukun Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Yu Han
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Shuo Wu
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
| | - Jiaojiao Pang
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Qiuhuan Yuan
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital of Shandong University, Jinan (J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., J.P., Q.Y.)
| | - Bailu Wang
- National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Clinical Trial Center, Qilu Hospital of Shandong University, Jinan, China (B.W.)
| | - Feng Xu
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
| | - Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
- Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital of Shandong University, Jinan, China (X.Z., S.C., J.W., B.Q., X.L., R.H., M.Z., S.S., Y.H., S.W., J.P., Q.Y., F.X., S.W., Y.C.)
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11
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Ababneh H, Balogh E, Csiki DM, Lente G, Fenyvesi F, Tóth A, Jeney V. High glucose promotes osteogenic differentiation of human lens epithelial cells through hypoxia-inducible factor (HIF) activation. J Cell Physiol 2024; 239:e31211. [PMID: 38304971 DOI: 10.1002/jcp.31211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 01/17/2024] [Accepted: 01/22/2024] [Indexed: 02/03/2024]
Abstract
Cataract, a leading cause of blindness, is characterised by lens opacification. Type 2 diabetes is associated with a two- to fivefold higher prevalence of cataracts. The risk of cataract formation increases with the duration of diabetes and the severity of hyperglycaemia. Hydroxyapatite deposition is present in cataractous lenses that could be the consequence of osteogenic differentiation and calcification of lens epithelial cells (LECs). We hypothesised that hyperglycaemia might promote the osteogenic differentiation of human LECs (HuLECs). Osteogenic medium (OM) containing excess phosphate and calcium with normal (1 g/L) or high (4.5 g/L) glucose was used to induce HuLEC calcification. High glucose accelerated and intensified OM-induced calcification of HuLECs, which was accompanied by hyperglycaemia-induced upregulation of the osteogenic markers Runx2, Sox9, alkaline phosphatase and osteocalcin, as well as nuclear translocation of Runx2. High glucose-induced calcification was abolished in Runx2-deficient HuLECs. Additionally, high glucose stabilised the regulatory alpha subunits of hypoxia-inducible factor 1 (HIF-1), triggered nuclear translocation of HIF-1α and increased the expression of HIF-1 target genes. Gene silencing of HIF-1α or HIF-2α attenuated hyperglycaemia-induced calcification of HuLECs, while hypoxia mimetics (desferrioxamine, CoCl2) enhanced calcification of HuLECs under normal glucose conditions. Overall, this study suggests that high glucose promotes HuLEC calcification via Runx2 and the activation of the HIF-1 signalling pathway. These findings may provide new insights into the pathogenesis of diabetic cataracts, shedding light on potential factors for intervention to treat this sight-threatening condition.
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Affiliation(s)
- Haneen Ababneh
- Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Enikő Balogh
- Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Dávid Máté Csiki
- Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Gréta Lente
- Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Ferenc Fenyvesi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
| | - Andrea Tóth
- Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Viktória Jeney
- Research Centre for Molecular Medicine, MTA-DE Lendület Vascular Pathophysiology Research Group, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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12
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Merra G, Dominici F, Gualtieri P, Capacci A, Cenname G, Esposito E, Dri M, Di Renzo L, Marchetti M. Role of vitamin K2 in bone-vascular crosstalk. INT J VITAM NUTR RES 2024; 94:143-152. [PMID: 36039403 DOI: 10.1024/0300-9831/a000761] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Vitamin K (VK) is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs). It has been shown to play an important role in the proper calcium deposit at the bone level, hindering that on the vascular walls. The deficiency of this vitamin in European populations is frequent and unknown. It is related to several factors, poor dietary intake, altered intestinal absorption or altered production by bacteria, indicating possible dysbiosis. For Vitamin K2 (VK2), there is currently no official reference daily intake (RDI). However, the effects of VK2 on the improvement of health in cardiovascular diseases, on bone metabolism, on chronic kidney diseases have been the subject of research in recent decades. The microbiota in the gastrointestinal tract plays an important role: Bacteroides are primarily capable of synthetizing very long chain forms of menaquinones and, in addition to the bacteria present in the intestinal flora, VK2 is also produced by bacteria used in food fermentation processes. This review provides an update on the current literature regarding the origin of VK2 and its implications in what is called the "calcium paradox", namely the lack of calcium in the bone and its storage in the wall of the vessel.
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Affiliation(s)
- Giuseppe Merra
- Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Francesca Dominici
- Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Paola Gualtieri
- Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Annunziata Capacci
- Department of Medical and Surgical Sciences, Agostino Gemelli General Hospital Foundation-IRCCS, Rome, Italy
| | - Giuseppe Cenname
- Comando Generale Arma Carabinieri, Direzione di Sanità, Rome, Italy
| | - Ernesto Esposito
- General Directorate, Department of Human Policies of Basilicata Region, Potenza, Italy
| | - Maria Dri
- Department of Surgical Sciences, School of Applied Medical-Surgical Sciences, University of Rome Tor Vergata, Rome, Italy
| | - Laura Di Renzo
- Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Marco Marchetti
- Section of Clinical Nutrition and Nutrigenomic, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
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13
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Kauffenstein G, Martin L, Le Saux O. The Purinergic Nature of Pseudoxanthoma Elasticum. BIOLOGY 2024; 13:74. [PMID: 38392293 PMCID: PMC10886499 DOI: 10.3390/biology13020074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/13/2024] [Accepted: 01/19/2024] [Indexed: 02/24/2024]
Abstract
Pseudoxanthoma Elasticum (PXE) is an inherited disease characterized by elastic fiber calcification in the eyes, the skin and the cardiovascular system. PXE results from mutations in ABCC6 that encodes an ABC transporter primarily expressed in the liver and kidneys. It took nearly 15 years after identifying the gene to better understand the etiology of PXE. ABCC6 function facilitates the efflux of ATP, which is sequentially hydrolyzed by the ectonucleotidases ENPP1 and CD73 into pyrophosphate (PPi) and adenosine, both inhibitors of calcification. PXE, together with General Arterial Calcification of Infancy (GACI caused by ENPP1 mutations) as well as Calcification of Joints and Arteries (CALJA caused by NT5E/CD73 mutations), forms a disease continuum with overlapping phenotypes and shares steps of the same molecular pathway. The explanation of these phenotypes place ABCC6 as an upstream regulator of a purinergic pathway (ABCC6 → ENPP1 → CD73 → TNAP) that notably inhibits mineralization by maintaining a physiological Pi/PPi ratio in connective tissues. Based on a review of the literature and our recent experimental data, we suggest that PXE (and GACI/CALJA) be considered as an authentic "purinergic disease". In this article, we recapitulate the pathobiology of PXE and review molecular and physiological data showing that, beyond PPi deficiency and ectopic calcification, PXE is associated with wide and complex alterations of purinergic systems. Finally, we speculate on the future prospects regarding purinergic signaling and other aspects of this disease.
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Affiliation(s)
- Gilles Kauffenstein
- UMR INSERM 1260, Regenerative Nanomedicine, University of Strasbourg, 67084 Strasbourg, France
| | - Ludovic Martin
- PXE Consultation Center, MAGEC Nord Reference Center for Rare Skin Diseases, Angers University Hospital, 49000 Angers, France
- MITOVASC-UMR CNRS 6015 INSERM 1083, University of Angers, 49000 Angers, France
| | - Olivier Le Saux
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96822, USA
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14
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Fang YP, Zhao Y, Huang JY, Yang X, Liu Y, Zhang XL. The functional role of cellular senescence during vascular calcification in chronic kidney disease. Front Endocrinol (Lausanne) 2024; 15:1330942. [PMID: 38318291 PMCID: PMC10839002 DOI: 10.3389/fendo.2024.1330942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/03/2024] [Indexed: 02/07/2024] Open
Abstract
Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases.
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Affiliation(s)
- Ya-Ping Fang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yu Zhao
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Jia-Yi Huang
- Department of Clinical Medicine, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xin Yang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yan Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xiao-Liang Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
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15
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Blümm C, Bonaterra GA, Schwarzbach H, Eiden LE, Weihe E, Kinscherf R. PAC1 deficiency reduces chondrogenesis in atherosclerotic lesions of hypercholesterolemic ApoE-deficient mice. BMC Cardiovasc Disord 2023; 23:566. [PMID: 37980508 PMCID: PMC10657554 DOI: 10.1186/s12872-023-03600-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 11/07/2023] [Indexed: 11/20/2023] Open
Abstract
BACKGROUND Induction of chondrogenesis is associated with progressive atherosclerosis. Deficiency of the ADCYAP1 gene encoding pituitary adenylate cyclase-activating peptide (PACAP) aggravates atherosclerosis in ApoE deficient (ApoE-/-) mice. PACAP signaling regulates chondrogenesis and osteogenesis during cartilage and bone development. Therefore, this study aimed to decipher whether PACAP signaling is related to atherogenesis-related chondrogenesis in the ApoE-/- mouse model of atherosclerosis and under the influence of a high-fat diet. METHODS For this purpose, PACAP-/-/ApoE-/-, PAC1-/-/ApoE-/-, and ApoE-/- mice, as well as wildtype (WT) mice, were studied under standard chow (SC) or cholesterol-enriched diet (CED) for 20 weeks. The amount of cartilage matrix in atherosclerotic lesions of the brachiocephalic trunk (BT) with maximal lumen stenosis was monitored by alcian blue and collagen II staining on deparaffinized cross sections. The chondrogenic RUNX family transcription factor 2 (RUNX2), macrophages [(MΦ), Iba1+], and smooth muscle cells (SMC, sm-α-actin) were immunohistochemically analyzed and quantified. RESULTS ApoE-/- mice fed either SC or CED revealed an increase of alcian blue-positive areas within the media compared to WT mice. PAC1-/-/ApoE-/- mice under CED showed a reduction in the alcian blue-positive plaque area in the BT compared to ApoE-/- mice. In contrast, PACAP deficiency in ApoE-/- mice did not affect the chondrogenic signature under either diet. CONCLUSIONS Our data show that PAC1 deficiency reduces chondrogenesis in atherosclerotic plaques exclusively under conditions of CED-induced hypercholesterolemia. We conclude that CED-related chondrogenesis occurs in atherosclerotic plaques via transdifferentiation of SMCs and MΦ, partly depending on PACAP signaling through PAC1. Thus, PAC1 antagonists or PACAP agonists may offer therapeutic potential against pathological chondrogenesis in atherosclerotic lesions generated under hypercholesterolemic conditions, especially in familial hypercholesterolemia. This discovery opens therapeutic perspectives to be used in the treatment against the progression of atherosclerosis.
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Affiliation(s)
- C Blümm
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - G A Bonaterra
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany.
| | - H Schwarzbach
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - L E Eiden
- Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health Intramural Research Program, Bethesda, MD, 20814, USA
| | - E Weihe
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
| | - R Kinscherf
- Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032, Marburg, Germany
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Abstract
The medial layer of the arterial wall is composed mainly of vascular smooth muscle cells (VSMCs). Under physiological conditions, VSMCs assume a contractile phenotype, and their primary function is to regulate vascular tone. In contrast with terminally differentiated cells, VSMCs possess phenotypic plasticity, capable of transitioning into other cellular phenotypes in response to changes in the vascular environment. Recent research has shown that VSMC phenotypic switching participates in the pathogenesis of atherosclerosis, where the various types of dedifferentiated VSMCs accumulate in the atherosclerotic lesion and participate in the associated vascular remodeling by secreting extracellular matrix proteins and proteases. This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs. It also provides an overview of several methodologies that have been developed for studying VSMC phenotypic switching and discusses their respective advantages and limitations.
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Affiliation(s)
- Runji Chen
- Shantou University Medical CollegeShantouChina
| | - David G. McVey
- Department of Cardiovascular SciencesUniversity of LeicesterLeicesterUnited Kingdom
| | - Daifei Shen
- Research Center for Translational MedicineThe Second Affiliated Hospital of Shantou University Medical CollegeShantouChina
| | | | - Shu Ye
- Shantou University Medical CollegeShantouChina
- Department of Cardiovascular SciencesUniversity of LeicesterLeicesterUnited Kingdom
- Cardiovascular‐Metabolic Disease Translational Research ProgrammeNational University of SingaporeSingapore
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17
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Li XZ, Xiong ZC, Zhang SL, Hao QY, Liu ZY, Zhang HF, Wang JF, Gao JW, Liu PM. Upregulated LncRNA H19 Sponges MiR-106a-5p and Contributes to Aldosterone-Induced Vascular Calcification via Activating the Runx2-Dependent Pathway. Arterioscler Thromb Vasc Biol 2023; 43:1684-1699. [PMID: 37409531 DOI: 10.1161/atvbaha.123.319308] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 06/19/2023] [Indexed: 07/07/2023]
Abstract
BACKGROUND Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.
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Affiliation(s)
- Xiong-Zhi Li
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Now with Cardiovascular Department, the First Affiliated Hospital of Shaoyang University, Hunan, China (X.-Z.L.)
| | - Zhuo-Chao Xiong
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shao-Ling Zhang
- Department of Endocrinology (S.-L.Z.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing-Yun Hao
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhao-Yu Liu
- Medical Research Center (Z.-Y.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hai-Feng Zhang
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing-Feng Wang
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing-Wei Gao
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Pin-Ming Liu
- Department of Cardiology, Guangzhou Key Laboratory on the Molecular Mechanisms of Major Cardiovascular Disease, Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology (X.-Z.L., Z.-C.X., Q.-Y.H., H.-F.Z., J.-F.W., J.-W.G., P.-M.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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18
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Boix-Lemonche G, Nagymihaly RM, Lumi X, Petrovski G. The human lens is capable of trilineage differentiation towards osteo-, chondro-, and adipogenesis-a model for studying cataract pathogenesis. Front Bioeng Biotechnol 2023; 11:1164795. [PMID: 37324433 PMCID: PMC10264667 DOI: 10.3389/fbioe.2023.1164795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/18/2023] [Indexed: 06/17/2023] Open
Abstract
The potential for trilineage differentiation of cells in tissues represents a model for studying disease pathogenesis and regeneration pathways. Human lens trilineage differentiation has not yet been demonstrated, and so has calcification and osteogenic differentiation of human lens epithelial cells in the whole human lens. Such changes can pose a risk for complications during cataract surgery. Human lens capsules (n = 9) from cataract patients undergoing uneventful surgery were trilineage-differentiated toward osteogenesis, chondrogenesis, and adipogenesis. Furthermore, whole human healthy lenses (n = 3) collected from cadaveric eyes were differentiated into bone and characterized by immunohistochemistry. The cells in the human lens capsules were capable of undergoing trilineage differentiation, while the whole human healthy lenses could undergo osteogenesis differentiation, expressing osteocalcin, collagen I, and pigment epithelium-derived factor. We, hereby, show an ex vivo model for cataract formation through different stages of opacification, as well as provide in vivo evidence from patients undergoing calcified lens extraction with bone-like consistency.
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Affiliation(s)
- Gerard Boix-Lemonche
- Department of Ophthalmology, Center for Eye Research and Innovative Diagnostics, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | | | - Xhevat Lumi
- Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
- Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Goran Petrovski
- Department of Ophthalmology, Center for Eye Research and Innovative Diagnostics, Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
- Department of Ophthalmology, University of Split School of Medicine and University Hospital Centre, Split, Croatia
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Si SC, Yang W, Luo HY, Ma YX, Zhao H, Liu J. Association of bone turnover biomarkers with severe intracranial and extracranial artery stenosis in type 2 diabetes mellitus patients. World J Diabetes 2023; 14:594-605. [PMID: 37273245 PMCID: PMC10236991 DOI: 10.4239/wjd.v14.i5.594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/20/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Intracranial and extracranial artery stenosis is associated with cerebral infarction. Vascular calcification and atherosclerosis are the main causes of stenosis and major risk factors for cardiovascular and cerebrovascular events in patients with type 2 diabetes mellitus (T2DM). Bone turnover biomarkers (BTMs) are associated with vascular calcification, atherosclerosis, glucose, and lipid metabolism.
AIM To investigate the association of circulating BTM levels with severe intracranial and extracranial artery stenosis in patients with T2DM.
METHODS For this cross-sectional study including 257 T2DM patients, levels of the BTMs serum osteocalcin (OC), C-terminal cross-linked telopeptide of type I collagen (CTX), and procollagen type I N-peptide were measured by electrical chemiluminescent immunoassay, and artery stenosis was assessed by color Doppler and transcranial Doppler. Patients were grouped according to the existence and location (intracranial vs. extracranial) of artery stenosis. Correlations between BTM levels, previous stroke, stenosis location, and glucose and lipid metabolism were analyzed.
RESULTS T2DM patients with severe artery stenosis had a higher frequency of previous stroke and levels of all three tested BTMs (all P < 0.05) than patients without. Some differences in OC and CTX levels were observed according to the location of artery stenosis. Significant associations were also observed between BTM levels and some glucose and lipid homeostasis parameters. On multivariate logistic regression analysis, all BTMs were significant predictors of artery stenosis in T2DM patients with and without adjustment for confounding factors (all P < 0.001), and receiver operating characteristic curve analysis demonstrated the ability of BTM levels to predict artery stenosis in T2DM patients.
CONCLUSION BTM levels were found to be independent risk factors for severe intracranial and extracranial artery stenosis and were differentially associated with glucose and lipid metabolism in patients with T2DM. Therefore, BTMs may be promising biomarkers and potential therapeutic targets for artery stenosis.
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Affiliation(s)
- Si-Cong Si
- General Geriatric Department, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Wei Yang
- General Geriatric Department, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Hong-Yu Luo
- General Geriatric Department, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Yi-Xin Ma
- General Geriatric Department, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Huan Zhao
- General Geriatric Department, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
| | - Jia Liu
- General Geriatric Department, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
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Sakamoto A, Kawakami R, Mori M, Guo L, Paek KH, Mosquera JV, Cornelissen A, Ghosh SKB, Kawai K, Konishi T, Fernandez R, Fuller DT, Xu W, Vozenilek AE, Sato Y, Jinnouchi H, Torii S, Turner AW, Akahori H, Kuntz S, Weinkauf CC, Lee PJ, Kutys R, Harris K, Killey AL, Mayhew CM, Ellis M, Weinstein LM, Gadhoke NV, Dhingra R, Ullman J, Dikongue A, Romero ME, Kolodgie FD, Miller CL, Virmani R, Finn AV. CD163+ macrophages restrain vascular calcification, promoting the development of high-risk plaque. JCI Insight 2023; 8:e154922. [PMID: 36719758 PMCID: PMC10077470 DOI: 10.1172/jci.insight.154922] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 01/20/2023] [Indexed: 02/01/2023] Open
Abstract
Vascular calcification (VC) is concomitant with atherosclerosis, yet it remains uncertain why rupture-prone high-risk plaques do not typically show extensive calcification. Intraplaque hemorrhage (IPH) deposits erythrocyte-derived cholesterol, enlarging the necrotic core and promoting high-risk plaque development. Pro-atherogenic CD163+ alternative macrophages engulf hemoglobin:haptoglobin (HH) complexes at IPH sites. However, their role in VC has never been examined to our knowledge. Here we show, in human arteries, the distribution of CD163+ macrophages correlated inversely with VC. In vitro experiments using vascular smooth muscle cells (VSMCs) cultured with HH-exposed human macrophage - M(Hb) - supernatant reduced calcification, while arteries from ApoE-/- CD163-/- mice showed greater VC. M(Hb) supernatant-exposed VSMCs showed activated NF-κB, while blocking NF-κB attenuated the anticalcific effect of M(Hb) on VSMCs. CD163+ macrophages altered VC through NF-κB-induced transcription of hyaluronan synthase (HAS), an enzyme that catalyzes the formation of the extracellular matrix glycosaminoglycan, hyaluronan, within VSMCs. M(Hb) supernatants enhanced HAS production in VSMCs, while knocking down HAS attenuated its anticalcific effect. NF-κB blockade in ApoE-/- mice reduced hyaluronan and increased VC. In human arteries, hyaluronan and HAS were increased in areas of CD163+ macrophage presence. Our findings highlight an important mechanism by which CD163+ macrophages inhibit VC through NF-κB-induced HAS augmentation and thus promote the high-risk plaque development.
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Affiliation(s)
| | | | | | - Liang Guo
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | - Ka Hyun Paek
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | - Jose Verdezoto Mosquera
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA
| | | | | | - Kenji Kawai
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | | | | | | | - Weili Xu
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | | | - Yu Sato
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | | | - Sho Torii
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | - Adam W. Turner
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Hirokuni Akahori
- Department of Cardiovascular and Renal Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Salome Kuntz
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | - Craig C. Weinkauf
- Division of Vascular and Endovascular Surgery, University of Arizona, Tucson, Arizona, USA
| | | | - Robert Kutys
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | - Kathryn Harris
- University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | | | | | | | | | - Roma Dhingra
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | | | | | | | | | - Clint L. Miller
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USA
| | - Renu Virmani
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
| | - Aloke V. Finn
- CVPath Institute, Inc., Gaithersburg, Maryland, USA
- University of Maryland School of Medicine, Baltimore, Maryland, USA
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21
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Sun J, Zhang Z, Fei Y, Gao Y, Li Z, Gao S, Wang Y, Liu J, Tu J, Wang H, Wang J, Ning X, Zhao W, Zhang W. Determinants of arterial elastic function in middle-aged and elderly people: A population-based cross-sectional study from a low-income population in China. Front Cardiovasc Med 2023; 10:1037227. [PMID: 36844726 PMCID: PMC9949891 DOI: 10.3389/fcvm.2023.1037227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/25/2023] [Indexed: 02/11/2023] Open
Abstract
Background Arterial stiffness is closely associated with the occurrence of many cardiovascular and cerebrovascular diseases. However, the risk factors and mechanisms related to arterial stiffness development have only been partially elucidated. We aimed to describe arterial elastic function and its influencing factors in middle-aged and elderly people in rural China. Methods This was a cross-sectional study conducted among residents, aged ≥45 years, of Tianjin, China, between April and July 2015. Data regarding participant demographics, medical history, lifestyle, and physical examination results were collected and assessed the association with arterial elastic function using linear regression. Results Of the 3,519 participants, 1,457 were male (41.4%). Brachial artery distensibility (BAD) decreased by 0.5%/mmHg with every 10-year increment in age. The mean BAD value was 0.864%/mmHg lower in women than in men. With each unit increase in mean arterial pressure, the BAD decreased by 0.042%/mmHg. In patients with hypertension or diabetes, the BAD decreased by 0.726 and 0.183%/mmHg, respectively, compared with those without hypertension or diabetes. For each unit increase in triglyceride (TG) level, the mean BAD increased by 0.043%/mmHg. With each increase in body mass index (BMI) category, the BAD increased by 0.113%/mmHg. Brachial artery compliance (BAC) decreased by 0.007 ml/mmHg with each 10-year increase in age, and brachial artery resistance (BAR) increased by 30.237 dyn s-1 cm-5. The mean BAC in women was 0.036 ml/mmHg lower and the mean BAR was 155.231 dyn s-1 cm-5 higher in women than in men. In individuals with hypertension, the mean BAC decreased by 0.009 ml/mmHg and the mean BAR increased by 26.169 dyn s-1 cm-5. With each increase in BMI category, the mean BAC increased by 0.005 ml/mmHg and the mean BAR decreased by 31.345 dyn s-1 cm-5. For each unit increase in TG level, the mean BAC increased by 0.001 ml/mmHg. Conclusion These findings indicate that age, sex, mean arterial pressure, BMI, diabetes, hypertension, and TG level are independently associated with the components of peripheral arterial elasticity. Understanding the factors influencing arterial stiffness is important for developing interventions to minimize arterial aging and cardiovascular and cerebrovascular diseases caused by arterial aging.
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Affiliation(s)
- Jiayi Sun
- Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zhen Zhang
- Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Yunhan Fei
- Department of Emergency, Tianjin Huanhu Hospital, Tianjin, China
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, China
| | - Yannan Gao
- Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Zejian Li
- Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shuai Gao
- School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Yunfan Wang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jie Liu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jun Tu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Epidemiology, Tianjin Neurological Institute, Tianjin, China
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tianjin Jizhou People’s Hospital, Tianjin, China
| | - Haiying Wang
- Department of Cardiology, Tianjin Jizhou People’s Hospital, Tianjin, China
| | - Jinghua Wang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
- Laboratory of Epidemiology, Tianjin Neurological Institute, Tianjin, China
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, China
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tianjin Jizhou People’s Hospital, Tianjin, China
| | - Xianjia Ning
- Institute of Clinical Epidemiology and Evidence-Based Medicine, Tianjin Jizhou People’s Hospital, Tianjin, China
| | - Wenjuan Zhao
- Department of Emergency, Tianjin Huanhu Hospital, Tianjin, China
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, China
| | - Wenjuan Zhang
- Department of Cardiology, Tianjin Medical University General Hospital, Tianjin, China
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22
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Liu Z, Tong T, Sun J, Wu W, Zhang J, Cui Z, Han M. Piezo1 in endothelial cells is involved in vitamin D-induced vascular calcification. Biochem Biophys Res Commun 2023; 638:140-146. [PMID: 36455360 DOI: 10.1016/j.bbrc.2022.11.060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/06/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022]
Abstract
The relationship between the Piezo1 channel of vascular endothelial cells and vascular calcification is unknown. In this study, after subcutaneous injection of vitamin D for 10 consecutive days, the mice showed an increase in serum calcium, aortic calcium content, vascular tension and pulse wave velocity. Piezo1channel antagonist, GsMTx4 alleviated arteriosclerosis and decreased the aortic calcium content, while Piezo1 agonist Yoda1 produced opposite effect. In addition, activation of Piezo1 by Yoda1 impaired the function of human umbilical vein endothelial cells (HUVECs), as evidenced by further decreased production of NO, reduction in expression levels of eNOS, MMP-2, PCNA and VEGFA. When co-culture of HUVECs and vascular smooth muscle cells (VSMCs), activation of Piezo1 in HUVECs enhanced expression levels of calcification-related SOX9 and Runx2 genes, increased ALP activity and calcium deposition in VSMCs. We concluded that Piezo1 in endothelial cells is involved in the pathogenesis of vascular calcification. This study provides a new experimental basis for the prevention and treatment of vascular calcification.
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Affiliation(s)
- Zhihui Liu
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China
| | - Tong Tong
- Department of Spine Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China
| | - Jinglei Sun
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Wenting Wu
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Jiali Zhang
- Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Ziyang Cui
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China
| | - Mei Han
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China.
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23
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Phadwal K, Koo E, Jones RA, Forsythe RO, Tang K, Tang Q, Corcoran BM, Caporali A, MacRae VE. Metformin protects against vascular calcification through the selective degradation of Runx2 by the p62 autophagy receptor. J Cell Physiol 2022; 237:4303-4316. [PMID: 36166694 DOI: 10.1002/jcp.30887] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 09/04/2022] [Accepted: 09/06/2022] [Indexed: 11/09/2022]
Abstract
Vascular calcification is associated with aging, type 2 diabetes, and atherosclerosis, and increases the risk of cardiovascular morbidity and mortality. It is an active, highly regulated process that resembles physiological bone formation. It has previously been established that pharmacological doses of metformin alleviate arterial calcification through adenosine monophosphate-activated protein kinase (AMPK)-activated autophagy, however the specific pathway remains elusive. In the present study we hypothesized that metformin protects against arterial calcification through the direct autophagic degradation of runt-related transcription factor 2 (Runx2). Calcification was blunted in vascular smooth muscle cells (VSMCs) by metformin in a dose-dependent manner (0.5-1.5 mM) compared to control cells (p < 0.01). VSMCs cultured under high-phosphate (Pi) conditions in the presence of metformin (1 mM) showed a significant increase in LC3 puncta following bafilomycin-A1 (Baf-A; 5 nM) treatment compared to control cells (p < 0.001). Furthermore, reduced expression of Runx2 was observed in the nuclei of metformin-treated calcifying VSMCs (p < 0.0001). Evaluation of the functional role of autophagy through Atg3 knockdown in VSMCs showed aggravated Pi-induced calcification (p < 0.0001), failure to induce autophagy (punctate LC3) (p < 0.001) and increased nuclear Runx2 expression (p < 0.0001) in VSMCs cultured under high Pi conditions in the presence of metformin (1 mM). Mechanistic studies employing three-way coimmunoprecipitation with Runx2, p62, and LC3 revealed that p62 binds to both LC3 and Runx2 upon metformin treatment in VSMCs. Furthermore, immunoblotting with LC3 revealed that Runx2 specifically binds with p62 and LC3-II in metformin-treated calcified VSMCs. Lastly, we investigated the importance of the autophagy pathway in vascular calcification in a clinical setting. Ex vivo clinical analyses of calcified diabetic lower limb artery tissues highlighted a negative association between Runx2 and LC3 in the vascular calcification process. These studies suggest that exploitation of metformin and its analogues may represent a novel therapeutic strategy for clinical intervention through the induction of AMPK/Autophagy Related 3 (Atg3)-dependent autophagy and the subsequent p62-mediated autophagic degradation of Runx2.
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Affiliation(s)
- Kanchan Phadwal
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Eve Koo
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Ross A Jones
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Edinburgh, UK
| | - Rachael O Forsythe
- Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Department of Vascular Surgery, Edinburgh Royal Infirmary, Edinburgh, UK
| | - Keyi Tang
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Qiyu Tang
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Brendan M Corcoran
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
| | - Andrea Caporali
- Centre for Cardiovascular Science, The Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Vicky E MacRae
- The Roslin Institute and R(D)SVS, The University of Edinburgh, Edinburgh, UK
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24
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Yu Q, Liu JX, Zheng X, Yan X, Zhao P, Yin C, Li W, Song Z. Sox9 mediates autophagy-dependent vascular smooth muscle cell phenotypic modulation and transplant arteriosclerosis. iScience 2022; 25:105161. [PMID: 36204267 PMCID: PMC9531173 DOI: 10.1016/j.isci.2022.105161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 08/04/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Qihong Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
- Clinical Medical Research Center of Hepatic Surgery at Hubei Province, Wuhan 430030, China
| | - Jin-Xin Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xichuan Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xueke Yan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Peng Zhao
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chuanzheng Yin
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Li
- Departments of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Corresponding author
| | - Zifang Song
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Corresponding author
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25
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[miRNA-26a reduces vascular smooth muscle cell calcification by regulating connective tissue growth factor]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2022; 42:1303-1308. [PMID: 36210702 PMCID: PMC9550542 DOI: 10.12122/j.issn.1673-4254.2022.09.05] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVE To investigate the regulatory role of miRNA-26a in vascular smooth muscle cell (VSMC) calcification by regulating connective tissue growth factor (CTGF). METHODS Rat thoracic aorta VSMCs (A7r5 cells) with induced calcification were treated with AR234960 agonist or transfected with miR-26a mimic, or with both treatments. Alizarin red staining was used to determine calcium deposition, and phosphatase (ALP) activity in the cells was measured. The mRNA and protein expressions of miR-26a, OPG, OPN, BMP-2 and collagen Ⅱ were detected using qPCR and Western blotting. The binding of miR-26a to CTGF was verified using dual luciferase reporter gene assay. RESULTS After induced calcification, A7r5 cells showed gradually decreased miR-26a expression (P < 0.05) and progressively increased CTGF expression (P < 0.05) with the extension of induction time. Treatment of the cells with AR234960 obviously increased calcification in the cells, while transfection with miR-26a mimic significantly reduced cell calcification. The calcifying cells showed significantly increased ALP activity and expressions of OPN, BMP-2 and collagen Ⅱ (P < 0.05) and lowered OPG expression (P < 0.05), and treatment with AR234960 did not produce obvious effects on these changes (P > 0.05). Transfection with miR-26a mimic resulted in significantly decreased ALP activity and expressions OPN, BMP-2 and collagen Ⅱ expression (P < 0.05) and increased OPG expression (P < 0.05) in the calcifying cells. These effects of miR-26a mimic was significantly attenuated by treatment of the cells with AR234960 (P < 0.05). The result of luciferase reporter gene assay confirmed the binding of miR-26a to CTGF. CONCLUSION miRNA-26a can effectively alleviate vascular calcification by lowering the level of CTGF, reducing ALP activity and the expressions of OPN, BMP-2 and collagen Ⅱ, and increasing the expression of OPG.
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26
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Arterial stiffness and atrial fibrillation: shared mechanisms, clinical implications and therapeutic options. J Hypertens 2022; 40:1639-1646. [PMID: 35943096 DOI: 10.1097/hjh.0000000000003223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Arterial stiffness (AS) and atrial fibrillation (AF) share commonalities in molecular and pathophysiological mechanisms and numerous studies have analyzed their reciprocal influence. The gold standard for AS diagnosis is represented by aortic pulse wave velocity, whose measurement can be affected by arrhythmias characterized by irregularities in heart rhythm, such as AF. Growing evidence show that patients with AS are at high risk of AF development. Moreover, the subset of AF patients with AS seems to be more symptomatic and rhythm control strategies are less effective in this population. Reducing AS through de-stiffening interventions may be beneficial for patients with AF and can be a new appealing target for the holistic approach of AF management. In this review, we discuss the association between AS and AF, with particular interest in shared mechanisms, clinical implications and therapeutic options.
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27
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Identification of microRNAs related with neural germ layer lineage-specific progenitors during reprogramming. J Mol Histol 2022; 53:623-634. [DOI: 10.1007/s10735-022-10082-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/26/2022] [Indexed: 11/24/2022]
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28
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Ouyang L, Yu C, Xie Z, Su X, Xu Z, Song P, Li J, Huang H, Ding Y, Zou MH. Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification. Circulation 2022; 145:1784-1798. [PMID: 35582948 PMCID: PMC9197997 DOI: 10.1161/circulationaha.121.057868] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 04/20/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification. METHODS We generated global Apoe (apolipoprotein E) and Ido1 double knockout mice, and Apoe knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model. RESULTS Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/-Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification. CONCLUSIONS Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.
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Affiliation(s)
- Liu Ouyang
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Changjiang Yu
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Zhiyong Xie
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Su
- Department of Nephropathy, Tungwah Hospital of Sun Yat-sen University, Sun Yat-sen University, Dongguan, China
| | - Zengmei Xu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China
| | - Ping Song
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Jian Li
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China
| | - Ye Ding
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
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Ying KE, Feng W, Ying WZ, Li X, Xing D, Sun Y, Chen Y, Sanders PW. Dietary salt initiates redox signaling between endothelium and vascular smooth muscle through NADPH oxidase 4. Redox Biol 2022; 52:102296. [PMID: 35378363 PMCID: PMC8980891 DOI: 10.1016/j.redox.2022.102296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 03/16/2022] [Indexed: 11/19/2022] Open
Abstract
Prevention of phenotype switching of vascular smooth muscle cells is an important determinant of normal vascular physiology. Hydrogen peroxide (H2O2) promotes osteogenic differentiation of vascular smooth muscle cells through expression of Runt related transcription factor 2 (Runx2). In this study, an increase in dietary NaCl increased endothelial H2O2 generation through NOX4, a NAD(P)H oxidase. The production of H2O2 was sufficient to increase Runx2, osteopontin and osteocalcin in adjacent vascular smooth muscle cells from control littermate mice but was inhibited in mice lacking endothelial Nox4. A vascular smooth muscle cell culture model confirmed the direct involvement of the activation of protein kinase B (Akt) with inactivation of FoxO1 and FoxO3a observed in the control mice on the high NaCl diet. The present study also showed a reduction of catalase activity in aortas during high NaCl intake. The findings demonstrated an interesting cell-cell communication in the vascular wall that was initiated with H2O2 production by endothelium and was regulated by dietary NaCl intake. A better understanding of how dietary salt intake alters vascular biology may improve treatment of vascular disease that involves activation of Runx2.
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Affiliation(s)
- Kai Er Ying
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA
| | - Wenguang Feng
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA
| | - Wei-Zhong Ying
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA
| | - Xingsheng Li
- Department of Urology, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA
| | - Dongqi Xing
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA
| | - Yong Sun
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA
| | - Yabing Chen
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Birmingham Department of Veterans Affairs Health Care System, Birmingham, AL, 35233, USA
| | - Paul W Sanders
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Birmingham Department of Veterans Affairs Health Care System, Birmingham, AL, 35233, USA.
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Leenders NHJ, Bos C, Hoekstra T, Schurgers LJ, Vervloet MG, Hoenderop JGJ. Dietary magnesium supplementation inhibits abdominal vascular calcification in an experimental animal model of chronic kidney disease. Nephrol Dial Transplant 2022; 37:1049-1058. [PMID: 35134986 PMCID: PMC9130027 DOI: 10.1093/ndt/gfac026] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Vascular calcification is a key process involved in cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Magnesium supplementation may counteract vascular calcification. In this study we aimed to determine whether increased dietary magnesium intake inhibits vascular calcification in CKD in vivo and explore the mechanisms underlying these effects. METHODS Sprague Dawley rats were partially nephrectomized and fed a diet with high phosphate and either high or normal magnesium content for 16 weeks. The primary outcome was the tissue calcium content of the aorta in the high versus normal dietary magnesium group. In addition, we analysed plasma mineral concentrations, aortic vascular calcification identified with von Kossa staining, calcium apposition time and aortic expression of genes related to vascular calcification. RESULTS The number of animals in the highest tissue calcium content tertile was significantly lower in the abdominal aorta [1 (10%) versus 6 (55%); P = .03] in the high versus normal dietary magnesium group, but did not differ in the aortic arch and thoracic aorta. Von Kossa staining and calcium apposition time corresponded to these results. The median tissue calcium content was not significantly different between the groups. Serum phosphate concentrations and expression of osteogenic markers in the aorta did not differ between the groups. CONCLUSIONS This study demonstrates that increased dietary magnesium inhibits abdominal vascular calcification in an experimental animal model of CKD in vivo. These are promising results for CKD patients and further study is needed to identify the mechanisms involved and to determine the clinical relevance in patients.
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Affiliation(s)
- Nicoline H J Leenders
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Caro Bos
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Tiny Hoekstra
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Leon J Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Marc G Vervloet
- Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Wen W, Gao M, Yun M, Meng J, Yu W, Zhu Z, Tian Y, Mou T, Zhang Y, Hacker M, Li S, Yu Y, Li X, Zhang X. In Vivo Coronary 18F-Sodium Fluoride Activity: Correlations With Coronary Plaque Histological Vulnerability and Physiological Environment. JACC. CARDIOVASCULAR IMAGING 2022; 16:508-520. [PMID: 36648038 DOI: 10.1016/j.jcmg.2022.03.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 01/18/2023]
Abstract
OBJECTIVES This prospective study aimed to evaluate the associations between in vivo coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) activity and ex vivo histological characteristics, to determine whether coronary 18F-NaF activity is a novel biomarker of plaque pathological vulnerability, and to explore the underlying physiological environment of 18F-NaF adsorption to vascular microcalcification. BACKGROUND 18F-NaF PET/CT is a promising new approach for assessing microcalcification in vascular plaque. METHODS Patients with coronary artery disease (CAD) underwent coronary computed tomography angiography (CTA) and 18F-NaF PET/CT. Histological vulnerability and immunohistochemical characteristics were evaluated in coronary endarterectomy (CE) specimens from patients who underwent coronary artery bypass grafting with adjunctive CE. Correlations between in-vivo coronary 18F-NaF activity with coronary CTA adverse plaque features and with ex vivo CE specimen morphological features, CD68 expression, inflammatory cytokines expression (tumor necrosis factor-α, interleukin-1β), osteogenic differentiation cytokines expression (osteopontin, runt-related transcription factor 2, osteocalcin) were evaluated. High- and low- to medium-risk plaques were defined by standard pathological classification. RESULTS A total of 55 specimens were obtained from 42 CAD patients. Coronary 18F-NaF activity of high-risk specimens was significantly higher than low- to medium-risk specimens (median [25th-75th percentile]: 1.88 [1.41-2.54] vs 1.12 [0.91-1.54]; P < 0.001). Coronary 18F-NaF activity showed high discriminatory accuracy in identifying high-risk plaque (AUC 0.80). Coronary CTA adverse plaque features (positive remodeling, low-attenuation plaque, remodeling index), histologically vulnerable features (large necrotic core, thin-fibro cap, microcalcification), CD68 expression, tumor necrosis factor-α expression, and interleukin-1β expression correlated with coronary 18F-NaF activity (all P < 0.05). No significant association between coronary 18F-NaF activity and osteogenic differentiation cytokines was found (all P > 0.05). CONCLUSIONS Coronary 18F-NaF activity was associated with histological vulnerability, CD68 expression, inflammatory cytokines expression, but not with osteogenic differentiation cytokines expression. 18F-NaF PET/CT imaging may provide a powerful tool for detecting high-risk coronary plaque and could improve the risk stratification of CAD patients.
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Affiliation(s)
- Wanwan Wen
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Mingxin Gao
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Mingkai Yun
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jingjing Meng
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Wenyuan Yu
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Ziwei Zhu
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yi Tian
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Tiantian Mou
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yandong Zhang
- Department of Pathology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Marcus Hacker
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Vienna General Hospital, Medical University of Vienna, Vienna, Austria
| | - Sijin Li
- Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yang Yu
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
| | - Xiang Li
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China; Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Vienna General Hospital, Medical University of Vienna, Vienna, Austria.
| | - Xiaoli Zhang
- Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
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Dai X, Liu S, Cheng L, Huang T, Guo H, Wang D, Xia M, Ling W, Xiao Y. Epigenetic Upregulation of H19 and AMPK Inhibition Concurrently Contribute to S-Adenosylhomocysteine Hydrolase Deficiency-Promoted Atherosclerotic Calcification. Circ Res 2022; 130:1565-1582. [PMID: 35410483 DOI: 10.1161/circresaha.121.320251] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular disease; inhibition of SAH hydrolase (SAHH) results in SAH accumulation and induces endothelial dysfunction and atherosclerosis. However, the effect and mechanism of SAHH in atherosclerotic calcification is still unclear. We aimed to explore the role and mechanism of SAHH in atherosclerotic calcification. METHODS The relationship between SAHH and atherosclerotic calcification was investigated in patients with coronary atherosclerotic calcification. Different in vivo genetic models were used to examine the effect of SAHH deficiency on atherosclerotic calcification. Human aortic and murine vascular smooth muscle cells (VSMCs) were cultured to explore the underlying mechanism of SAHH on osteoblastic differentiation of VSMCs. RESULTS The expression and activity of SAHH were decreased in calcified human coronary arteries and inversely associated with coronary atherosclerotic calcification severity, whereas plasma SAH and total homocysteine levels were positively associated with coronary atherosclerotic calcification severity. Heterozygote knockout of SAHH promoted atherosclerotic calcification. Specifically, VSMC-deficient but not endothelial cell-deficient or macrophage-deficient SAHH promoted atherosclerotic calcification. Mechanistically, SAHH deficiency accumulated SAH levels and induced H19-mediated Runx2 (runt-related transcription factor 2)-dependent osteoblastic differentiation of VSMCs by inhibiting DNMT3b (DNA methyltransferase 3 beta) and leading to hypomethylation of the H19 promoter. On the other hand, SAHH deficiency resulted in lower intracellular levels of adenosine and reduced AMPK (AMP-activated protein kinase) activation. Adenosine supplementation activated AMPK and abolished SAHH deficiency-induced expression of H19 and Runx2 and osteoblastic differentiation of VSMCs. Finally, AMPK activation by adenosine inhibited H19 expression by inducing Sirt1-mediated histone H3 hypoacetylation and DNMT3b-mediated hypermethylation of the H19 promoter in SAHH deficiency VSMCs. CONCLUSIONS We have confirmed a novel correlation between SAHH deficiency and atherosclerotic calcification and clarified a new mechanism that epigenetic upregulation of H19 and AMPK inhibition concurrently contribute to SAHH deficiency-promoted Runx2-dependent atherosclerotic calcification.
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Affiliation(s)
- Xin Dai
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Si Liu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Lokyu Cheng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Ting Huang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
| | - Honghui Guo
- Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, China (H.G.)
| | - Dongliang Wang
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.)
| | - Min Xia
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.)
| | - Wenhua Ling
- Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.)
| | - Yunjun Xiao
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.)
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Wang S, Tang W, Zhou J, You F, Lei F, Yang Y, Zha X, Zhou Y. Combination of QCT and blood biochemistry for evaluating the relationship between nutrition and bone mineral density in patients on maintenance hemodialysis. J Ren Nutr 2022; 32:744-750. [DOI: 10.1053/j.jrn.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 01/02/2022] [Accepted: 03/19/2022] [Indexed: 11/11/2022] Open
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Gonçalves I, Oduor L, Matthes F, Rakem N, Meryn J, Skenteris NT, Aspberg A, Orho-Melander M, Nilsson J, Matic L, Edsfeldt A, Sun J, Bengtsson E. Osteomodulin Gene Expression Is Associated With Plaque Calcification, Stability, and Fewer Cardiovascular Events in the CPIP Cohort. Stroke 2022; 53:e79-e84. [PMID: 35135320 DOI: 10.1161/strokeaha.121.037223] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Stable atherosclerotic plaques are characterized by thick fibrous caps of smooth muscle cells, collagen, and macrocalcifications. Identifying factors of plaque stability is necessary to design drugs to prevent plaque rupture and symptoms. Osteomodulin, originally identified in bones, is expressed by bone synthesizing osteoblasts and involved in mineralization. In the present study, we analyzed osteomodulin expression in human carotid plaques, its link with plaque phenotype, calcification, and future cardiovascular events. METHODS Osteomodulin gene expression (OMD; n=82) was determined by RNA sequencing and osteomodulin protein levels by immunohistochemistry (n=45) in carotid plaques obtained by endarterectomy from patients with or without cerebrovascular symptoms from the CPIP (Carotid Plaque Imaging Project) cohort, Skåne University Hospital, Sweden. Plaque components were assessed by immunohistochemistry, RNA sequencing, and multiplex analysis. Patients were followed for cardiovascular events or cardiovascular death during a median of 57 or 70 months, respectively, using national registers. RESULTS OMD levels were increased in plaques from asymptomatic patients compared to symptomatics. High OMD levels were associated with fewer cardiovascular events during follow-up. OMD correlated positively with smooth muscle α-actin (ACTA2; r=0.73, P=10-13) and collagen (COL1A2; r=0.4, P=0.0002), but inversely with CD68 gene expression (r=-0.67, P=10-11), lipids (r=-0.37, P=0.001), intraplaque hemorrhage (r=-0.32, P=0.010), inflammatory cytokine, and matrix metalloproteinase plaque contents. OMD was positively associated with MSX2 (Msh Homeobox 2) (r=0.32, P=0.003), a marker of preosteoblast differentiation, BMP4 (bone morphogenetic protein) (r=0.50, P=0.000002) and BMP6 (r=0.47, P=0.000007), plaque calcification (r=0.35, P=0.016), and was strongly upregulated in osteogenically stimulated smooth muscle cells, which was further increased upon BMP stimulation. Osteomodulin protein was present in calcified regions. Osteomodulin protein levels were associated with plaque calcification (r=0.41, P=0.006) and increased in macrocalcified plaques. CONCLUSIONS These data show that osteomodulin mRNA and protein levels are associated with plaque calcification in human atherosclerosis. Furthermore, osteomodulin mRNA, but not protein levels, is associated with plaque stability.
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Affiliation(s)
- Isabel Gonçalves
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.).,Cardiology, Skåne University Hospital, Lund University, Sweden. (I.G., A.E.)
| | - Loureen Oduor
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
| | - Frank Matthes
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
| | - Narjess Rakem
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
| | - Jakob Meryn
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
| | - Nikolaos-Taxiarchis Skenteris
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.).,Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden (N.-T.S., L.M.)
| | - Anders Aspberg
- Department of Clinical Sciences, Lund University, Sweden. (A.A.)
| | | | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
| | - Ljubica Matic
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Sweden (N.-T.S., L.M.)
| | - Andreas Edsfeldt
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.).,Cardiology, Skåne University Hospital, Lund University, Sweden. (I.G., A.E.).,Wallenberg Centre for Molecular Medicine, Lund University, Sweden. (A.E.)
| | - Jiangming Sun
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
| | - Eva Bengtsson
- Department of Clinical Sciences Malmö, Lund University, Sweden. (I.G., L.O., F.M., N.R., J.M., M.O.-M., J.N., A.E., J.S., E.B.)
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Martin-Ventura JL, Roncal C, Orbe J, Blanco-Colio LM. Role of Extracellular Vesicles as Potential Diagnostic and/or Therapeutic Biomarkers in Chronic Cardiovascular Diseases. Front Cell Dev Biol 2022; 10:813885. [PMID: 35155428 PMCID: PMC8827403 DOI: 10.3389/fcell.2022.813885] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the first cause of death worldwide. In recent years, there has been great interest in the analysis of extracellular vesicles (EVs), including exosomes and microparticles, as potential mediators of biological communication between circulating cells/plasma and cells of the vasculature. Besides their activity as biological effectors, EVs have been also investigated as circulating/systemic biomarkers in different acute and chronic CVDs. In this review, the role of EVs as potential diagnostic and prognostic biomarkers in chronic cardiovascular diseases, including atherosclerosis (mainly, peripheral arterial disease, PAD), aortic stenosis (AS) and aortic aneurysms (AAs), will be described. Mechanistically, we will analyze the implication of EVs in pathological processes associated to cardiovascular remodeling, with special emphasis in their role in vascular and valvular calcification. Specifically, we will focus on the participation of EVs in calcium accumulation in the pathological vascular wall and aortic valves, involving the phenotypic change of vascular smooth muscle cells (SMCs) or valvular interstitial cells (IC) to osteoblast-like cells. The knowledge of the implication of EVs in the pathogenic mechanisms of cardiovascular remodeling is still to be completely deciphered but there are promising results supporting their potential translational application to the diagnosis and therapy of different CVDs.
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Affiliation(s)
- Jose Luis Martin-Ventura
- Vascular Research Laboratory, IIS-Fundación Jiménez-Díaz, Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- *Correspondence: Jose Luis Martin-Ventura, ; Carmen Roncal,
| | - Carmen Roncal
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- *Correspondence: Jose Luis Martin-Ventura, ; Carmen Roncal,
| | - Josune Orbe
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - Luis Miguel Blanco-Colio
- Vascular Research Laboratory, IIS-Fundación Jiménez-Díaz, Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Li T, Yu H, Zhang D, Feng T, Miao M, Li J, Liu X. Matrix Vesicles as a Therapeutic Target for Vascular Calcification. Front Cell Dev Biol 2022; 10:825622. [PMID: 35127686 PMCID: PMC8814528 DOI: 10.3389/fcell.2022.825622] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/04/2022] [Indexed: 01/01/2023] Open
Abstract
Vascular calcification (VC) is linked to an increased risk of heart disease, stroke, and atherosclerotic plaque rupture. It is a cell-active process regulated by vascular cells rather than pure passive calcium (Ca) deposition. In recent years, extracellular vesicles (EVs) have attracted extensive attention because of their essential role in the process of VC. Matrix vesicles (MVs), one type of EVs, are especially critical in extracellular matrix mineralization and the early stages of the development of VC. Vascular smooth muscle cells (VSMCs) have the potential to undergo phenotypic transformation and to serve as a nucleation site for hydroxyapatite crystals upon extracellular stimulation. However, it is not clear what underlying mechanism that MVs drive the VSMCs phenotype switching and to result in calcification. This article aims to review the detailed role of MVs in the progression of VC and compare the difference with other major drivers of calcification, including aging, uremia, mechanical stress, oxidative stress, and inflammation. We will also bring attention to the novel findings in the isolation and characterization of MVs, and the therapeutic application of MVs in VC.
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Affiliation(s)
- Tiantian Li
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Hongchi Yu
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Demao Zhang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Tang Feng
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
| | - Michael Miao
- Division of Oral & Craniofacial Health Sciences, University of North Carolina Adams School of Dentistry, Chapel Hill, NC, United States
| | - Jianwei Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Jianwei Li, ; Xiaoheng Liu,
| | - Xiaoheng Liu
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
- *Correspondence: Jianwei Li, ; Xiaoheng Liu,
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Goettsch C, Strzelecka-Kiliszek A, Bessueille L, Quillard T, Mechtouff L, Pikula S, Canet-Soulas E, Luis MJ, Fonta C, Magne D. TNAP as a therapeutic target for cardiovascular calcification: a discussion of its pleiotropic functions in the body. Cardiovasc Res 2022; 118:84-96. [PMID: 33070177 PMCID: PMC8752354 DOI: 10.1093/cvr/cvaa299] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/11/2020] [Accepted: 10/06/2020] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular calcification (CVC) is associated with increased morbidity and mortality. It develops in several diseases and locations, such as in the tunica intima in atherosclerosis plaques, in the tunica media in type 2 diabetes and chronic kidney disease, and in aortic valves. In spite of the wide occurrence of CVC and its detrimental effects on cardiovascular diseases (CVD), no treatment is yet available. Most of CVC involve mechanisms similar to those occurring during endochondral and/or intramembranous ossification. Logically, since tissue-nonspecific alkaline phosphatase (TNAP) is the key-enzyme responsible for skeletal/dental mineralization, it is a promising target to limit CVC. Tools have recently been developed to inhibit its activity and preclinical studies conducted in animal models of vascular calcification already provided promising results. Nevertheless, as its name indicates, TNAP is ubiquitous and recent data indicate that it dephosphorylates different substrates in vivo to participate in other important physiological functions besides mineralization. For instance, TNAP is involved in the metabolism of pyridoxal phosphate and the production of neurotransmitters. TNAP has also been described as an anti-inflammatory enzyme able to dephosphorylate adenosine nucleotides and lipopolysaccharide. A better understanding of the full spectrum of TNAP's functions is needed to better characterize the effects of TNAP inhibition in diseases associated with CVC. In this review, after a brief description of the different types of CVC, we describe the newly uncovered additional functions of TNAP and discuss the expected consequences of its systemic inhibition in vivo.
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Affiliation(s)
- Claudia Goettsch
- Department of Internal Medicine I, Cardiology, Medical Faculty, RWTH Aachen
University, Aachen, Germany
| | - Agnieszka Strzelecka-Kiliszek
- Laboratory of Biochemistry of Lipids, Nencki Institute of Experimental
Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
| | - Laurence Bessueille
- Institute of Molecular and Supramolecular Chemistry and Biochemistry
(ICBMS), UMR CNRS 5246, Université Claude Bernard Lyon 1, Bâtiment
Raulin, 43 Bd du 11 novembre 1918, Lyon 69622 Villeurbanne Cedex, France
| | - Thibaut Quillard
- PHY-OS Laboratory, UMR 1238 INSERM, Université de Nantes, CHU
de Nantes, France
| | - Laura Mechtouff
- Stroke Department, Hospices Civils de Lyon, France
- CREATIS Laboratory, CNRS UMR 5220, Inserm U1044, Université Claude Bernard
Lyon 1, Lyon, France
| | - Slawomir Pikula
- Laboratory of Biochemistry of Lipids, Nencki Institute of Experimental
Biology, 3 Pasteur Street, 02-093 Warsaw, Poland
| | - Emmanuelle Canet-Soulas
- CarMeN Laboratory, Univ Lyon, INSERM, INRA, INSA Lyon, Université Claude
Bernard Lyon 1, Lyon, France
| | - Millan Jose Luis
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery
Institute, La Jolla, CA 92037, USA
| | - Caroline Fonta
- Brain and Cognition Research Center CerCo, CNRS UMR5549, Université de
Toulouse, France
| | - David Magne
- Institute of Molecular and Supramolecular Chemistry and Biochemistry
(ICBMS), UMR CNRS 5246, Université Claude Bernard Lyon 1, Bâtiment
Raulin, 43 Bd du 11 novembre 1918, Lyon 69622 Villeurbanne Cedex, France
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Lage JGB, Bortolotto AL, Scanavacca MI, Bortolotto LA, Darrieux FCDC. Arterial stiffness and atrial fibrillation: A review. Clinics (Sao Paulo) 2022; 77:100014. [PMID: 35248986 PMCID: PMC8903742 DOI: 10.1016/j.clinsp.2022.100014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/30/2021] [Indexed: 01/07/2023] Open
Abstract
Arterial stiffness has been investigated as part of the physiopathology of arterial hypertension since the 1970s. Its role in increasing the "pulsatile load" imposed over the Left Ventricle (LV) has been intensely studied recently and has helped in understanding the mechanisms of Atrial Fibrillation (AF) in hypertensive patients. This paper aims to review the main evidence on this issue and establish possible mechanisms involved in the development of AF in patients with arterial stiffness. A PubMed search was performed, and selected articles were searched for references focusing on this topic. In the long term, lower blood pressure levels allow for arterial wall remodeling, leading to a lower stiffness index. To this day, however, there are no available treatments that directly promote the lowering of arterial wall stiffness. Most classes of anti-hypertensive drugs ‒ with stronger evidence for beta-blockers and diuretics ‒ could be effective in reducing arterial stiffness. There is strong evidence demonstrating an association between arterial stiffness and AF. New studies focusing on arterial stiffness and pre-fibrillatory stages would strengthen this causality relation.
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Affiliation(s)
- João Gabriel Batista Lage
- Instituto do Coração (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil.
| | - Alexandre Lemos Bortolotto
- Instituto do Coração (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Mauricio Ibrahim Scanavacca
- Instituto do Coração (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | - Luiz Aparecido Bortolotto
- Instituto do Coração (InCor), Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
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Shreya D, Zamora DI, Patel GS, Grossmann I, Rodriguez K, Soni M, Joshi PK, Patel SC, Sange I. Coronary Artery Calcium Score - A Reliable Indicator of Coronary Artery Disease? Cureus 2021; 13:e20149. [PMID: 35003981 PMCID: PMC8723785 DOI: 10.7759/cureus.20149] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/03/2021] [Indexed: 11/16/2022] Open
Abstract
Coronary artery disease (CAD) is caused by atheromatous blockage of coronary vessels leading to acute coronary events that usually occur when a plaque ruptures and a thrombus forms. CAD is a known cause of significant cardiovascular events, accounting for more than 50% of the deaths in western countries, and most of the patients with CAD remain asymptomatic. The coronary artery calcium (CAC) score has been created as a measure of coronary atherosclerosis. This article has compiled various studies that conclude the clinical relationship between coronary artery calcium and the development of cardiovascular (CV) events by using the CAC score as a reliable indicator of CAD. This article has reviewed the pathophysiology and risk factors of CAD, along with various methods of CAC scoring. It also underlined the reliability of CAC scoring for early detection of CAD in asymptomatic individuals. We emphasized the importance of age-dependent risk factor analysis combined with practical screening tools like CAC scoring for early diagnosis of CAD can help direct the treatment and prevent deaths in asymptomatic individuals.
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Xie F, Cui QK, Wang ZY, Liu B, Qiao W, Li N, Cheng J, Hou YM, Dong XY, Wang Y, Zhang MX. ILF3 is responsible for hyperlipidemia-induced arteriosclerotic calcification by mediating BMP2 and STAT1 transcription. J Mol Cell Cardiol 2021; 161:39-52. [PMID: 34343541 DOI: 10.1016/j.yjmcc.2021.07.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/01/2021] [Accepted: 07/28/2021] [Indexed: 11/16/2022]
Abstract
Calcification is common in atherosclerotic plaque and can induce vulnerability, which further leads to myocardial infarction, plaque rupture and stroke. The mechanisms of atherosclerotic calcification are poorly characterized. Interleukin enhancer binding factor 3 (ILF3) has been identified as a novel factor affecting dyslipidemia and stroke subtypes. However, the precise role of ILF3 in atherosclerotic calcification remains unclear. In this study, we used smooth muscle-conditional ILF3 knockout (ILF3SM-KO) and transgenic mice (ILF3SM-Tg) and macrophage-conditional ILF3 knockout (ILF3M-KO) and transgenic (ILF3M-Tg) mice respectively. Here we showed that ILF3 expression is increased in calcified human aortic vascular smooth muscle cells (HAVSMCs) and calcified atherosclerotic plaque in humans and mice. We then found that hyperlipidemia increases ILF3 expression and exacerbates calcification of VSMCs and macrophages by regulating bone morphogenetic protein 2 (BMP2) and signal transducer and activator of transcription 1 (STAT1) transcription. We further explored the molecular mechanisms of ILF3 in atherosclerotic calcification and revealed that ILF3 acts on the promoter regions of BMP2 and STAT1 and mediates BMP2 upregulation and STAT1 downregulation, which promotes atherosclerotic calcification. Our results demonstrate the effect of ILF3 in atherosclerotic calcification. Inhibition of ILF3 may be a useful therapy for preventing and even reversing atherosclerotic calcification.
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Affiliation(s)
- Fei Xie
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qing-Ke Cui
- Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shandong, China
| | - Zhao-Yang Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bin Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wen Qiao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Na Li
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jie Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ya-Min Hou
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xin-Ying Dong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Wang
- Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Ming-Xiang Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Yap C, Mieremet A, de Vries CJ, Micha D, de Waard V. Six Shades of Vascular Smooth Muscle Cells Illuminated by KLF4 (Krüppel-Like Factor 4). Arterioscler Thromb Vasc Biol 2021; 41:2693-2707. [PMID: 34470477 PMCID: PMC8545254 DOI: 10.1161/atvbaha.121.316600] [Citation(s) in RCA: 163] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/20/2021] [Indexed: 12/23/2022]
Abstract
Multiple layers of vascular smooth muscle cells (vSMCs) are present in blood vessels forming the media of the vessel wall. vSMCs provide a vessel wall structure, enabling it to contract and relax, thus modulating blood flow. They also play a crucial role in the development of vascular diseases, such as atherosclerosis and aortic aneurysm formation. vSMCs display a remarkable high degree of plasticity. At present, the number of different vSMC phenotypes has only partially been characterized. By mapping vSMC phenotypes in detail and identifying triggers for phenotype switching, the relevance of the different phenotypes in vascular disease may be identified. Up until recently, vSMCs were classified as either contractile or dedifferentiated (ie, synthetic). However, single-cell RNA sequencing studies revealed such dedifferentiated arterial vSMCs to be highly diverse. Currently, no consensus exist about the number of vSMC phenotypes. Therefore, we reviewed the data from relevant single-cell RNA sequencing studies, and classified a total of 6 vSMC phenotypes. The central dedifferentiated vSMC type that we classified is the mesenchymal-like phenotype. Mesenchymal-like vSMCs subsequently seem to differentiate into fibroblast-like, macrophage-like, osteogenic-like, and adipocyte-like vSMCs, which contribute differentially to vascular disease. This phenotype switching between vSMCs requires the transcription factor KLF4 (Kruppel-like factor 4). Here, we performed an integrated analysis of the data about the recently identified vSMC phenotypes, their associated gene expression profiles, and previous vSMC knowledge to better understand the role of vSMC phenotype transitions in vascular pathology.
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Affiliation(s)
- Carmen Yap
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
| | - Arnout Mieremet
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
| | - Carlie J.M. de Vries
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
| | - Dimitra Micha
- Department of Clinical Genetics, Amsterdam Cardiovascular Sciences, Vrije Universiteit Amsterdam, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands (D.M.)
| | - Vivian de Waard
- Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam UMC, Location Academic Medical Center, The Netherlands (C.Y., A.M., C.J.M.d.V., V.d.W.)
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Dharmarajan S, Speer MY, Pierce K, Lally J, Leaf EM, Lin ME, Scatena M, Giachelli CM. Role of Runx2 in Calcific Aortic Valve Disease in Mouse Models. Front Cardiovasc Med 2021; 8:687210. [PMID: 34778386 PMCID: PMC8585763 DOI: 10.3389/fcvm.2021.687210] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 09/28/2021] [Indexed: 12/31/2022] Open
Abstract
Background: Calcific aortic valve disease is common in the aging population and is characterized by the histological changes of the aortic valves including extracellular matrix remodeling, osteochondrogenic differentiation, and calcification. Combined, these changes lead to aortic sclerosis, aortic stenosis (AS), and eventually to heart failure. Runt-related transcription factor 2 (Runx2) is a transcription factor highly expressed in the calcified aortic valves. However, its definitive role in the progression of calcific aortic valve disease (CAVD) has not been determined. In this study, we utilized constitutive and transient conditional knockout mouse models to assess the molecular, histological, and functional changes in the aortic valve due to Runx2 depletion. Methods: Lineage tracing studies were performed to determine the provenance of the cells giving rise to Runx2+ osteochondrogenic cells in the aortic valves of LDLr-/- mice. Hyperlipidemic mice with a constitutive or temporal depletion of Runx2 in the activated valvular interstitial cells (aVICs) and sinus wall cells were further investigated. Following feeding with a diabetogenic diet, the mice were examined for changes in gene expression, blood flow dynamics, calcification, and histology. Results: The aVICs and sinus wall cells gave rise to Runx2+ osteochondrogenic cells in diseased mouse aortic valves. The conditional depletion of Runx2 in the SM22α+ aVICs and sinus wall cells led to the decreased osteochondrogenic gene expression in diabetic LDLr-/- mice. The transient conditional depletion of Runx2 in the aVICs and sinus wall cells of LDLr-/-ApoB100 CAVD mice early in disease led to a significant reduction in the aortic peak velocity, mean velocity, and mean gradient, suggesting the causal role of Runx2 on the progression of AS. Finally, the leaflet hinge and sinus wall calcification were significantly decreased in the aortic valve following the conditional and temporal Runx2 depletion, but no significant effect on the valve cusp calcification or thickness was observed. Conclusions: In the aortic valve disease, Runx2 was expressed early and was required for the osteochondrogenic differentiation of the aVICs and sinus wall cells. The transient depletion of Runx2 in the aVICs and sinus wall cells in a mouse model of CAVD with a high prevalence of hemodynamic valve dysfunction led to an improved aortic valve function. Our studies also suggest that leaflet hinge and sinus wall calcification, even in the absence of significant leaflet cusp calcification, may be sufficient to cause significant valve dysfunctions in mice.
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Affiliation(s)
| | | | | | | | | | | | | | - Cecilia M. Giachelli
- Department of Bioengineering, University of Washington, Seattle, WA, United States
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Association between phosphate and long-term outcome in CAD patients underwent coronary intervention. Sci Rep 2021; 11:20080. [PMID: 34635717 PMCID: PMC8505547 DOI: 10.1038/s41598-021-99518-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/21/2021] [Indexed: 11/14/2022] Open
Abstract
Phosphate has been linked to higher cardiovascular (CV) risk. However, whether phosphate is associated with poor outcomes for patients with coronary artery disease (CAD) after percutaneous coronary interventions (PCIs) remained undetermined. 2,894 CAD patients (2,220 male, aged 71.6 ± 12.2), who received PCI at TVGH from 2006 to 2015, with phosphate measurement, were enrolled. The primary outcome was the composite of major adverse CV events [MACE, comprising of CV death, nonfatal MI, and nonfatal stroke] and heart failure hospitalization (HHF). The key secondary outcome was MACE. There was a J-curve association between phosphate and CV events after adjusted for comorbidities and renal function. Phosphate around 3.2 ± 0.1 mg/dL was associated with the lowest CV risk. In Cox analysis, each 1 mg/dL increases in phosphate was associated with a higher risk of MACE + HHF (HR: 1.12, 95% CI: 1.05–1.21): CV death (HR: 1.37, 95% CI: 1.22–1.55) and HHF (HR: 1.12, 95% CI: 1.02–1.23). Subgroup analyses showed more prominent association between phosphate and MACE + HHF in male, age > 65, bare-metal stents (BMSs), LVEF < 50%, eGFR < 60, LDL > 70 mg/dL, and emergent PCI. Phosphate has a significant association with the risk of CV events in CAD patients undergoing PCI that was independent of comorbidities and renal function.
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Dynamic Crosstalk between Vascular Smooth Muscle Cells and the Aged Extracellular Matrix. Int J Mol Sci 2021; 22:ijms221810175. [PMID: 34576337 PMCID: PMC8468233 DOI: 10.3390/ijms221810175] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/31/2021] [Accepted: 09/03/2021] [Indexed: 01/15/2023] Open
Abstract
Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases.
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Xiao F, Zha Q, Zhang Q, Wu Q, Chen Z, Yang Y, Yang K, Liu Y. Decreased Glucagon-Like Peptide-1 Is Associated With Calcific Aortic Valve Disease: GLP-1 Suppresses the Calcification of Aortic Valve Interstitial Cells. Front Cardiovasc Med 2021; 8:709741. [PMID: 34513952 PMCID: PMC8428521 DOI: 10.3389/fcvm.2021.709741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/23/2021] [Indexed: 12/25/2022] Open
Abstract
Objectives: This study explores the concentration and role of glucagon-like peptide-1 (GLP-1) in calcific aortic valve disease (CAVD). Background: Calcific aortic valve disease is a chronic disease presenting with aortic valve degeneration and mineralization. We hypothesized that the level of GLP-1 is associated with CAVD and that it participates in the calcification of aortic valve interstitial cells (AVICs). Methods: We compared the concentration of GLP-1 between 11 calcific and 12 normal aortic valve tissues by immunohistochemical (IHC) analysis. ELISA was used to measure GLP-1 in serum of the Control (n = 197) and CAVD groups (n = 200). The effect of GLP-1 on the calcification of AVICs and the regulation of calcific gene expression were also characterized. Results: The GLP-1 concentration in the calcific aortic valves was 39% less than that in the control non-calcified aortic valves. Its concentration in serum was 19.3% lower in CAVD patients. Multivariable regression analysis demonstrated that GLP-1 level was independently associated with CAVD risk. In vitro, GLP-1 antagonized AVIC calcification in a dose- and time-dependent manner and it down-regulated RUNX2, MSX2, BMP2, and BMP4 expression but up-regulated SOX9 expression. Conclusions: A reduction in GLP-1 was associated with CAVD, and GLP-1 participated in the mineralization of AVICs by regulating specific calcific genes. GLP-1 warrants consideration as a novel treatment target for CAVD.
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Affiliation(s)
- Fan Xiao
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qing Zha
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qianru Zhang
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Qihong Wu
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhongli Chen
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ying Yang
- Department of Endocrinology, The Second People's Hospital of Yunnan Province, Kunming, China
| | - Ke Yang
- Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yan Liu
- Department of Cardiology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice. Sci Rep 2021; 11:17851. [PMID: 34497344 PMCID: PMC8426400 DOI: 10.1038/s41598-021-97361-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/24/2021] [Indexed: 12/25/2022] Open
Abstract
Diabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.
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Korinfskaya S, Parameswaran S, Weirauch MT, Barski A. Runx Transcription Factors in T Cells-What Is Beyond Thymic Development? Front Immunol 2021; 12:701924. [PMID: 34421907 PMCID: PMC8377396 DOI: 10.3389/fimmu.2021.701924] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Runx proteins (also known as Runt-domain transcription factors) have been studied for a long time as key regulators of cellular differentiation. RUNX2 has been described as essential for osteogenesis, whereas RUNX1 and RUNX3 are known to control blood cell development during different stages of cell lineage specification. However, recent studies show evidence of complex relationships between RUNX proteins, chromatin-modifying machinery, the cytoskeleton and different transcription factors in various non-embryonic contexts, including mature T cell homeostasis, inflammation and cancer. In this review, we discuss the diversity of Runx functions in mature T helper cells, such as production of cytokines and chemokines by different CD4 T cell populations; apoptosis; and immunologic memory acquisition. We then briefly cover recent findings about the contribution of RUNX1, RUNX2 and RUNX3 to various immunologic diseases. Finally, we discuss areas that require further study to better understand the role that Runx proteins play in inflammation and immunity.
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Affiliation(s)
- Svetlana Korinfskaya
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Sreeja Parameswaran
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Matthew T Weirauch
- Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Artem Barski
- Division of Allergy & Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.,Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
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Zhang Y, Tang N, Zhou J. Intermedin1‑47 inhibits high phosphate‑induced vascular smooth muscle cell calcification by regulating Wnt/β‑catenin signaling. Mol Med Rep 2021; 24:733. [PMID: 34414455 DOI: 10.3892/mmr.2021.12373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 08/12/2019] [Indexed: 11/05/2022] Open
Abstract
Vascular calcification is a major risk factor for cardiovascular disease and accounts for a large proportion of deaths from cardiovascular disease in patients with chronic kidney disease. The high incidence, rapid progression and irreversibility of vascular smooth muscle cell (VSMC) calcification in patients has attracted attention. In the present study, the effect of intermedin1‑47 (IMD1‑47), an important isoform of intermedin, was investigated on the calcification of rat cardiovascular VSMCs induced by high phosphate (HP). To stimulate osteoblast‑like differentiation and calcification in rat VSMCs, 10 mM β‑sodium glycerophosphate was used. The VSMCs were then treated with three doses of IMD1‑47 and the effects of IMD1‑47 on VSMC calcification, on the expression of osteogenic markers [osteoprotegerin, Runt‑related transcription factor 2 (Runx2) and osteopontin (OPN)] and on alkaline phosphatase (ALP) activity were assessed. HP treatment significantly enhanced the cellular calcium content of VSMCs, the expression of osteogenic markers, and ALP activity, while IMD1‑47 significantly reversed these effects in a dose‑dependent manner. The protein expression levels of Wnt1, Wnt3a and active β‑catenin were determined and it was found that IMD1‑47 significantly inhibited their expression. Following β‑catenin silencing, the protein expression levels Runx2 and OPN were increased compared with the IMD1‑47 treatment alone, indicating a role for the Wnt/β‑catenin pathway in the effects of IMD1‑47 on osteogenic markers. The present study suggested that IMD1‑47 inhibited HP‑induced VSMC calcification by regulating the Wnt/β‑catenin signaling pathway.
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Affiliation(s)
- Yin Zhang
- Department of Geriatrics, Shanghai Fourth Rehabilitation Hospital, Shanghai 200042, P.R. China
| | - Naiwang Tang
- Department of Respiratory, Central Hospital of Xuhui District, Shanghai 200031, P.R. China
| | - Jinjie Zhou
- Department of Cardiology, Central Hospital of Huangpu District, Shanghai 200002, P.R. China
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Kumric M, Borovac JA, Ticinovic Kurir T, Martinovic D, Frka Separovic I, Baric L, Bozic J. Role of Matrix Gla Protein in the Complex Network of Coronary Artery Disease: A Comprehensive Review. Life (Basel) 2021; 11:737. [PMID: 34440481 PMCID: PMC8398385 DOI: 10.3390/life11080737] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/14/2021] [Accepted: 07/23/2021] [Indexed: 01/07/2023] Open
Abstract
Coronary artery disease (CAD) is widely recognized as one of the most important clinical entities. In recent years, a large body of accumulated data suggest that coronary artery calcification, a process highly prevalent in patients with CAD, occurs via well-organized biologic processes, rather than passively, as previously regarded. Matrix Gla protein (MGP), a vitamin K-dependent protein, emerged as an important inhibitor of both intimal and medial vascular calcification. The functionality of MGP hinges on two post-translational modifications: phosphorylation and carboxylation. Depending on the above-noted modifications, various species of MGP may exist in circulation, each with their respective level of functionality. Emerging data suggest that dysfunctional species of MGP, markedly, dephosphorylated-uncarboxylated MGP, might find its application as biomarkers of microvascular health, and assist in clinical decision making with regard to initiation of vitamin K supplementation. Hence, in this review we summarized the current knowledge with respect to the role of MGP in the complex network of vascular calcification with concurrent inferences to CAD. In addition, we discussed the effects of warfarin use on MGP functionality, with concomitant implications to coronary plaque stability.
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Affiliation(s)
- Marko Kumric
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (J.A.B.); (T.T.K.); (D.M.); (I.F.S.)
| | - Josip A. Borovac
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (J.A.B.); (T.T.K.); (D.M.); (I.F.S.)
- Department of Cardiology, University Hospital of Split, 21000 Split, Croatia
| | - Tina Ticinovic Kurir
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (J.A.B.); (T.T.K.); (D.M.); (I.F.S.)
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Hospital of Split, 21000 Split, Croatia
| | - Dinko Martinovic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (J.A.B.); (T.T.K.); (D.M.); (I.F.S.)
| | - Ivan Frka Separovic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (J.A.B.); (T.T.K.); (D.M.); (I.F.S.)
| | - Ljupka Baric
- Institute of Emergency Medicine of Split-Dalmatia County (ZHM SDZ), Spinčićeva 1, 21000 Split, Croatia;
| | - Josko Bozic
- Department of Pathophysiology, University of Split School of Medicine, 21000 Split, Croatia; (M.K.); (J.A.B.); (T.T.K.); (D.M.); (I.F.S.)
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Wang Y, Wang R, Liu Y, Bai L, Liu L, He L, Deng H, Li T, Xu S, Chen L, Wen K, Qi B. Associations between bone mineral density in different measurement locations and coronary artery disease: a cross-sectional study. Arch Osteoporos 2021; 16:100. [PMID: 34169345 DOI: 10.1007/s11657-021-00940-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 05/04/2021] [Indexed: 02/03/2023]
Abstract
UNLABELLED The bone mineral density (BMD) loss is closely related to coronary heart disease (CAD). The BMD measured at different locations differ in BMD values, the risk to CAD, and the capability to identify CAD. An average BMD of the right and left femoral neck being below - 1.70 has the ability to indicate risk of CAD. PURPOSE Previous studies have reported that low bone mineral density (BMD) is closely related to coronary artery disease (CAD); however, it is not clear that the BMD loss at which location to what extent has the greatest effect in identifying risk of CAD. This study aimed to evaluate the ability of different measurement sites of BMD in identifying CAD and analyze the best measurement sites and the optimal cut-off of BMD for CAD. METHODS This was a cross-sectional study in which 180 of 817 participants were diagnosed with CAD. All participants in the study were measured by dual-energy X-ray absorptiometry (DEXA) for BMD at 8 locations, and following measurements were derived: the average BMD of lumbar spine (L1-L4), femoral neck (left and right), and total proximal femur (left and right). The association between BMD at different locations and CAD was analyzed using logistic regression. The receiver operating characteristic (ROC) curve was used to select the optimal measurement location and cut-off value of the BMD for identifying CAD. RESULTS There were significant differences in BMD at 3 different measurement locations. Higher BMD is a protective factor against CAD, which is more pronounced in the femoral neck and total proximal femur (ORs = 0.47 ~ 0.66, P < 0.001) than in the lumbar spine (ORs = 0.74 ~ 0.79, P < 0.001). The optimal site for predicting the risk of CAD by BMD is the femoral neck, with the AUC (area under the ROC curve) is 0.72 (95% CI: 0.67 ~ 0.76) and the cut-off is - 1.70. CONCLUSION The BMD below particular cut-off of the femoral neck rather than of the lumbar spine may have certain further research value for revealing the risk of CAD.
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Affiliation(s)
- Yaoling Wang
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Ruiyun Wang
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Yun Liu
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Lijuan Bai
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Lihua Liu
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Linfeng He
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Heng Deng
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Tao Li
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Sha Xu
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Li Chen
- Novartis Pharmaceuticals Corporation, East Hanover, USA
| | - Kai Wen
- School of Software & Microelectronics, Peking University, Beijing, China
| | - Benling Qi
- Department of Geriatrics, Union Hospital of Tongji Medical College Huazhong University of Science & Technology, Wuhan, 430022, China.
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