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Jin Y, Zhang H. Comprehensive bioinformatics analysis uncover molecular pathways shared between osteoarthritis and atherosclerosis. BMC Musculoskelet Disord 2025; 26:449. [PMID: 40335993 PMCID: PMC12057041 DOI: 10.1186/s12891-025-08563-6] [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: 11/15/2023] [Accepted: 03/20/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND There is growing evidence of an association between osteoarthritis (OA) and atherosclerosis (AS). However, their mechanisms are not yet fully understood. The aim of this study was to investigate the common genetic and molecular mechanisms underlying the common pathogenesis of OA and AS. METHODOLOGY Gene expression profiles of OA (GSE51588) and AS (GSE100927) were obtained from the Gene Expression Omnibus (GEO) database. After identifying shared differentially expressed genes (DEGs) and hub genes, we performed multifaceted bioinformatics analyses, including functional annotation, co-expression analysis, TF-mRNA and ceRNA regulatory network construction, pharmacogenetic prediction, and receiver operator characteristic (ROC) curve assessment. In addition, the immune infiltration of OA and AS was analyzed and compared based on the ssGSEA algorithm, and the correlation between hub genes and infiltrating immune cells was evaluated in OA and AS, respectively. RESULT A total of 48 up-regulated and 43 down-regulated public DEGs were screened between GSE51588 and GSE100927, and functional enrichment analysis emphasized the important role of immune and inflammatory pathways in OA and AS. After protein-protein interaction (PPI) network construction, a total of 9 hub genes (CCR5, IFIT2, MMP1, CXCL9, RSAD2, IFIH1, TNF, IFIT3, and TBX21) were identified as key genes. Targeting the key genes we identified several molecular drug candidates against OA combined with AS related. Additionally diagnostic efficacy assessment using 9 central genes showed great diagnostic value (area under the curve from 0.710 to 0.973). Immune infiltration study also revealed coordinated changes in immune cell profiles in OA and AS diseases. CONCLUSION After a series of bioinformatics analysis and validation, CCR5, IFIT2, MMP1, CXCL9, RSAD2, IFIH1, TNF, IFIT3 and TBX21 were identified as common hub genes for the development of OA and AS. This study provides a new perspective on the common molecular mechanisms between OA and AS, and offers new insights into the potential pathogenesis of OA combined with AS and the direction of treatment.
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Affiliation(s)
- Yingchao Jin
- Department of orthopaedics, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Hua Zhang
- Department of orthopaedics, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
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Foote K, Rienks M, Schmidt L, Theofilatos K, Yasmin, Ozols M, Eckersley A, Shah A, Figg N, Finigan A, O’Shaughnessy K, Wilkinson I, Mayr M, Bennett M. Oxidative DNA damage promotes vascular ageing associated with changes in extracellular matrix-regulating proteins. Cardiovasc Res 2025; 121:614-628. [PMID: 38717632 PMCID: PMC12054627 DOI: 10.1093/cvr/cvae091] [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: 06/12/2023] [Revised: 01/31/2024] [Accepted: 02/29/2024] [Indexed: 02/13/2025] Open
Abstract
AIMS Vascular ageing is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular ageing, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular ageing. METHODS AND RESULTS We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of ageing, and ECM proteomics in mice from 22 to 72 w. Vascular ageing was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalized all parameters to 72 w. ECM proteomics identified major changes in collagens with ageing, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness. CONCLUSION Vascular ageing is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular ageing, associated with changes in ECM regulatory proteins including LOX and WISP2.
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MESH Headings
- Animals
- DNA Glycosylases/genetics
- DNA Glycosylases/metabolism
- DNA Glycosylases/deficiency
- Oxidative Stress
- DNA Damage
- Forkhead Box Protein O3/metabolism
- Extracellular Matrix Proteins/metabolism
- Extracellular Matrix Proteins/genetics
- Aging/metabolism
- Aging/pathology
- Aging/genetics
- Vascular Stiffness
- Mice, Knockout
- Mice, Inbred C57BL
- Male
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Muscle, Smooth, Vascular/physiopathology
- Humans
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/enzymology
- Signal Transduction
- Cells, Cultured
- Acetylation
- Extracellular Matrix/metabolism
- Mice
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Affiliation(s)
- Kirsty Foote
- Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK
| | - Marieke Rienks
- Cardiovascular Division, King’s College London, The James Black Centre, 2nd Floor, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Lukas Schmidt
- Cardiovascular Division, King’s College London, The James Black Centre, 2nd Floor, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Konstantinos Theofilatos
- Cardiovascular Division, King’s College London, The James Black Centre, 2nd Floor, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Yasmin
- Department of Medicine, Experimental Medicine and Therapeutics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 2QQ, UK
| | - Matiss Ozols
- Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1RQ, UK
| | - Alexander Eckersley
- Division of Musculoskeletal & Dermatological Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK
| | - Aarti Shah
- Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK
| | - Nichola Figg
- Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK
| | - Alison Finigan
- Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK
| | - Kevin O’Shaughnessy
- Department of Medicine, Experimental Medicine and Therapeutics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 2QQ, UK
| | - Ian Wilkinson
- Department of Medicine, Experimental Medicine and Therapeutics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 2QQ, UK
| | - Manuel Mayr
- Cardiovascular Division, King’s College London, The James Black Centre, 2nd Floor, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Martin Bennett
- Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK
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Whitehead M, Faleeva M, Oexner R, Cox S, Schmidt L, Mayr M, Shanahan CM. ECM Modifications Driven by Age and Metabolic Stress Directly Promote Vascular Smooth Muscle Cell Osteogenic Processes. Arterioscler Thromb Vasc Biol 2025; 45:424-442. [PMID: 39817328 PMCID: PMC11856005 DOI: 10.1161/atvbaha.124.321467] [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: 07/02/2024] [Revised: 12/03/2024] [Accepted: 12/23/2024] [Indexed: 01/18/2025]
Abstract
BACKGROUND The ECM (extracellular matrix) provides the microenvironmental niche sensed by resident vascular smooth muscle cells (VSMCs). Aging and disease are associated with dramatic changes in ECM composition and properties; however, their impact on VSMC phenotype remains poorly studied. METHODS Here, we describe a novel in vitro model system that utilizes endogenous ECM to study how modifications associated with age and metabolic disease impact VSMC phenotype. ECM was synthesized using primary human VSMCs and modified during culture or after decellularization. Integrity, stiffness, and composition of the ECM was measured using superresolution microscopy, atomic force microscopy, and proteomics, respectively. VSMCs reseeded onto the modified ECM were analyzed for viability and osteogenic differentiation. RESULTS ECMs produced in response to mineral stress showed extracellular vesicle-mediated hydroxyapatite deposition and sequential changes in collagen composition and ECM properties. VSMCs seeded onto the calcified ECM exhibited increased extracellular vesicle release and Runx2 (Runt-related transcription factor 2)-mediated osteogenic gene expression due to the uptake of hydroxyapatite, which led to increased reactive oxygen species and the induction of DNA damage signaling. VSMCs seeded onto the nonmineralized, senescent ECM also exhibited increased Runx2-mediated osteogenic gene expression and accelerated calcification. In contrast, glycated ECM specifically induced increased ALP (alkaline phosphatase) activity, and this was dependent on RAGE (receptor for advanced glycation end products) signaling with both ALP and RAGE receptor inhibition attenuating calcification. CONCLUSIONS ECM modifications associated with aging and metabolic disease can directly induce osteogenic differentiation of VSMCs via distinct mechanisms and without the need for additional stimuli. This highlights the importance of the ECM microenvironment as a key driver of phenotypic modulation acting to accelerate age-associated vascular pathologies and provides a novel model system to study the mechanisms of calcification.
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Affiliation(s)
- Meredith Whitehead
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.W., M.F., R.O., L.S., M.M., C.M.S.), King’s College London, United Kingdom
| | - Maria Faleeva
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.W., M.F., R.O., L.S., M.M., C.M.S.), King’s College London, United Kingdom
| | - Rafael Oexner
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.W., M.F., R.O., L.S., M.M., C.M.S.), King’s College London, United Kingdom
| | - Susan Cox
- Randall Centre for Cell & Molecular Biophysics, Faculty of Life Sciences & Medicine (S.C.), King’s College London, United Kingdom
| | - Lukas Schmidt
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.W., M.F., R.O., L.S., M.M., C.M.S.), King’s College London, United Kingdom
| | - Manuel Mayr
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.W., M.F., R.O., L.S., M.M., C.M.S.), King’s College London, United Kingdom
| | - Catherine M. Shanahan
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences (M.W., M.F., R.O., L.S., M.M., C.M.S.), King’s College London, United Kingdom
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Kim TH, Kim H, Lee HH, Sang JH. Vitamin K: Calcium Metabolism Modulator for Menopausal Women. J Menopausal Med 2024; 30:152-163. [PMID: 39829192 PMCID: PMC11745727 DOI: 10.6118/jmm.24023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 10/13/2024] [Accepted: 11/11/2024] [Indexed: 01/22/2025] Open
Abstract
Vitamin K (VitK) exists in multiple forms, with Vitamin K1 (VitK1) and Vitamin K2 (VitK2) being the most prominent. VitK1 primarily regulates clotting factors in the liver, whereas VitK2 plays a crucial role in activating extrahepatic proteins involved in various physiological processes. VitK plays a pivotal role in various physiological functions, including vascular health, bone metabolism, neuroprotection, hepatoprotection, immune response modulation, dental health, and glucose control. Particularly, activation of the matrix Gla protein and osteocalcin through VitK2 inhibits vascular calcification (VC) and promotes bone mineralization. This review provides an overview of the physiological functions of VitK2, underscoring its role in calcium metabolism modulation and its diverse effects on health. Additionally, this article provides a comprehensive overview of the beneficial functions of VitK, and discusses the significance of adequate dietary intake and oral supplementation of VitK. Particularly, emphasizing on the need for VitK2 supplementation owing to its relatively limited availability in Western diets. VitK2 supplementation effectively counters VC, enhances bone density, and offers neuroprotective, hepatoprotective, and anti-inflammatory benefits. Thus, the supplementation of VitK2, alongside dietary intake, is essential for preventive healthcare, particularly in the prevention of osteoporosis and vascular diseases. Incorporating adequate VitK2 intake highlights its significance in promoting overall well-being. Illustrated summary of the role of VitK in menopausal women.
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Affiliation(s)
- Tae-Hee Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Hayeon Kim
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Hae Hyeog Lee
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
| | - Jae Hong Sang
- Department of Obstetrics and Gynecology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
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Yu X, Xu L, Su C, Wang C, Wang Z, Wang Y, Lu X, Sun H. Luteolin Protects against Vascular Calcification by Modulating SIRT1/CXCR4 Signaling Pathway and Promoting Autophagy. AAPS J 2024; 26:111. [PMID: 39438407 DOI: 10.1208/s12248-024-00982-y] [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: 08/25/2024] [Accepted: 10/08/2024] [Indexed: 10/25/2024] Open
Abstract
Vascular calcification (VC) is a common pathological manifestation of atherosclerosis, hypertension, diabetes vascular disease, vascular injury, chronic kidney disease and aging, which is mainly manifested as increased stiffness of the vascular wall. Oxidative stress and autophagy dysfunction are key factors in the pathogenesis of vascular calcification, but the specific mechanisms and the therapeutic strategy of vascular calcification have not been clarified. In the present study, Sirtuin 1 (SIRT1) was screened as the therapeutic targets for vascular calcification by the bioinformatics. SIRT1 is a nicotinamide adenine dinucleotide, which plays an important role in inhibiting oxidative stress and promoting autophagy. Luteolin (LUT), a kind of natural tetrahydroxyl flavonoid, exists in many plants and has many pharmacological effects such as anti-oxidation and anti-apoptosis. We have reported that luteolin has certain anti-osteoporosis effects in the previous study, and it is accepted that the development of vascular calcification is similar to bone formation, indicating that luteolin may also resist vascular calcification. And luteolin is known to activate SIRT1 to some extent. Moreover, the molecular docking analysis predicted that SIRT1 could bind directly to luteolin. Therefore, the purpose of this study was to investigate the potential role of luteolin in inhibiting oxidative stress and promoting autophagy during vascular calcification via modulating SIRT1 expression. The results showed that luteolin significantly improved vascular calcification induced by a high-fat diet (HFD) and vitamin D3 in rats in vivo. In addition, luteolin significantly repressed the formation of mineralized nodules and ALP activity in H2O2-treated A7r5 cells. Luteolin reduced the level of MDA, LDH and ROS generation, inhibited the protein expression of cleaved caspase-3, cleaved caspase-9, β-catenin and BMP-2 in the aortic tissue of the rat and rat smooth muscle cells (A7r5) treated with hydrogen peroxide. At the same time, luteolin could promote the expression of autophagy related proteins. Moreover, luteolin also produced effects to increase the protein expression levels of SIRT1 more than 2 times both in vivo and in vitro. In terms of mechanism, luteolin attenuated vascular calcification by inhibiting oxidative stress and improving autophagy level, via modulating SIRT1 / CXCR4 signaling pathway. In conclusion, this experiment for the first time revealed that LUT protected against VC via modulating SIRT1 / CXCR4 signaling pathway to promote autophagy and inhibit vascular calcification and may be developed as a new therapeutic agent for vascular calcification and atherosclerosis.
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Affiliation(s)
- Xiaoyu Yu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China
| | - Lei Xu
- Office of Ethics Committee, the First Affiliated Hospital, Dalian Medical University, No. 222, Zhongshan Road, Xigang District, Dalian, 116011, China
| | - Ce Su
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China
| | - Changyuan Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China
| | - Zimeng Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China
| | - Yanna Wang
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China
| | - Xiaolong Lu
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.
| | - Huijun Sun
- Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China.
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6
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Gheorghe SR, Crăciun AM, Ilyés T, Tisa IB, Sur L, Lupan I, Samasca G, Silaghi CN. Converging Mechanisms of Vascular and Cartilaginous Calcification. BIOLOGY 2024; 13:565. [PMID: 39194503 DOI: 10.3390/biology13080565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 07/19/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024]
Abstract
Physiological calcification occurs in bones and epiphyseal cartilage as they grow, whereas ectopic calcification occurs in blood vessels, cartilage, and soft tissues. Although it was formerly thought to be a passive and degenerative process associated with aging, ectopic calcification has been identified as an active cell-mediated process resembling osteogenesis, and an increasing number of studies have provided evidence for this paradigm shift. A significant association between vascular calcification and cardiovascular risk has been demonstrated by various studies, which have shown that arterial calcification has predictive value for future coronary events. With respect to cartilaginous calcification, calcium phosphate or hydroxyapatite crystals can form asymptomatic deposits in joints or periarticular tissues, contributing to the pathophysiology of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, tendinitis, and bursitis. The risk factors and sequence of events that initiate ectopic calcification, as well as the mechanisms that prevent the development of this pathology, are still topics of debate. Consequently, in this review, we focus on the nexus of the mechanisms underlying vascular and cartilaginous calcifications, trying to circumscribe the similarities and disparities between them to provide more clarity in this regard.
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Affiliation(s)
- Simona R Gheorghe
- Department of Medical Biochemistry, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Alexandra M Crăciun
- Department of Medical Biochemistry, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Tamás Ilyés
- Department of Medical Biochemistry, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Ioana Badiu Tisa
- Department of Pediatrics III, Iuliu Hatieganu University of Medicine and Pharmacy, 400217 Cluj-Napoca, Romania
| | - Lucia Sur
- Department of Pediatrics I, Iuliu Hatieganu University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania
| | - Iulia Lupan
- Department of Molecular Biology, Babes-Bolyai University, 400084 Cluj-Napoca, Romania
| | - Gabriel Samasca
- Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Ciprian N Silaghi
- Department of Medical Biochemistry, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
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Tao J, Wang J, Peng H, Yuan Y, Lai H, Gu P, Xier Z, Li G, Yang YN. Association between serum phosphate, magnesium, calcium and aortic valve sclerosis: a propensity score-matched case-control study. Acta Cardiol 2024; 79:522-529. [PMID: 39041382 DOI: 10.1080/00015385.2024.2379682] [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: 04/28/2024] [Revised: 06/14/2024] [Accepted: 07/05/2024] [Indexed: 07/24/2024]
Abstract
OBJECTIVES Aortic valve sclerosis has been proposed to signify greater cardiovascular risk; the correlation between serum trace elements and aortic valve sclerosis has been reported. Therefore, an in-depth exploration of the risk factors for aortic valve sclerosis and early intervention may reduce the risk of cardiovascular disease. METHODS In this study, Patients with aortic valve sclerosis and non-aortic valve sclerosis who underwent echocardiographic diagnosis in the People's Hospital of Xinjiang Uygur Autonomous Region during the period from 2019 to 2021 were selected for this study. The correlation between aortic valve sclerosis and serum phosphorus, calcium, and magnesium levels was explored using the propensity score matching technique by pairing the two groups of patients 1:1. RESULTS A total of 1,533 non-aortic valve sclerosis and 1,533 aortic valve sclerosis patients were included. Logistic regression analysis showed that serum magnesium [OR: 0.346; 95%CI: 0.227, 0.528] and serum calcium [OR: 7.022; 95%CI: 4.755, 10.369] were influential factors. Patients with low, intermediate, and high serum magnesium levels had a significantly lower risk of aortic valve sclerosis compared to patients with very low micronutrient levels (p < 0.05). Comparatively, patients with low or high serum calcium levels had an elevated risk of aortic valve sclerosis (p < 0.05). CONCLUSION Serum magnesium may have a protective role against aortic valve sclerosis, while both low and high levels of serum calcium could be risk factor for the condition. These serum micronutrients may be indications of cardiovascular disease risk prediction or prevention, and more research is required.
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Affiliation(s)
- Jing Tao
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Juan Wang
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Hui Peng
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Yujuan Yuan
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Hongmei Lai
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Peipei Gu
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Zulipiyemu Xier
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Guoqing Li
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
| | - Yi-Ning Yang
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang, China
- Department of Cardiovascular Medicine, Xinjiang Uygur Autonomous Region People's Hospital, Urumqi, Xinjiang, China
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8
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Murali S, Smith ER, Tiong MK, Tan S, Toussaint ND. Interventions to Attenuate Cardiovascular Calcification Progression: A Systematic Review of Randomized Clinical Trials. J Am Heart Assoc 2023; 12:e031676. [PMID: 38014685 PMCID: PMC10727339 DOI: 10.1161/jaha.123.031676] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/23/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Cardiovascular calcification, characterized by deposition of calcium phosphate in the arterial wall and heart valves, is associated with cardiovascular morbidity and mortality and is commonly seen in aging, diabetes, and chronic kidney disease. Whether evidence-based interventions could significantly attenuate cardiovascular calcification progression remains uncertain. METHODS AND RESULTS We conducted a systematic review of randomized controlled trials involving interventions, compared with placebo, another comparator, or standard of care, to attenuate cardiovascular calcification. Included clinical trials involved participants without chronic kidney disease, and the outcome was cardiovascular calcification measured using radiological methods. Quality of evidence was determined by the Cochrane risk of bias and Grading of Recommendations, Assessment, Development, and Evaluations assessment. Forty-nine randomized controlled trials involving 9901 participants (median participants 104, median duration 12 months) were eligible for inclusion. Trials involving aged garlic extract (n=6 studies) consistently showed attenuation of cardiovascular calcification. Trials involving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (n=14), other lipid-lowering agents (n=2), hormone replacement therapies (n=3), vitamin K (n=5), lifestyle measures (n=4), and omega-3 fatty acids (n=2) consistently showed no attenuation of cardiovascular calcification with these therapies. Trials involving antiresorptive (n=2), antihypertensive (n=2), antithrombotic (n=4), and hypoglycemic agents (n=3) showed mixed results. Singleton studies involving salsalate, folate with vitamin B6 and 12, and dalcetrapib showed no attenuation of cardiovascular calcification. Overall, Cochrane risk of bias was moderate, and the Grading of Recommendations, Assessment, Development, and Evaluations assessment for a majority of analyses was moderate certainty of evidence. CONCLUSIONS Currently, there are insufficient or conflicting data for interventions evaluated in clinical trials for mitigation of cardiovascular calcification. Therapy involving aged garlic extract appears most promising, but evaluable studies were small and of short duration.
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Affiliation(s)
- Shashank Murali
- Department of NephrologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
| | - Edward R. Smith
- Department of NephrologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
- Department of Medicine (RMH)University of MelbourneParkvilleVictoriaAustralia
| | - Mark K. Tiong
- Department of NephrologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
- Department of Medicine (RMH)University of MelbourneParkvilleVictoriaAustralia
| | - Sven‐Jean Tan
- Department of NephrologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
- Department of Medicine (RMH)University of MelbourneParkvilleVictoriaAustralia
| | - Nigel D. Toussaint
- Department of NephrologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
- Department of Medicine (RMH)University of MelbourneParkvilleVictoriaAustralia
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Shrestha SK, Kim SW, Soh Y. Kalkitoxin attenuates calcification of vascular smooth muscle cells via RUNX-2 signaling pathways. J Vet Sci 2023; 24:e69. [PMID: 38031648 PMCID: PMC10556282 DOI: 10.4142/jvs.23148] [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: 06/05/2023] [Revised: 07/21/2023] [Accepted: 08/07/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Kalkitoxin (KT) is an active lipopeptide isolated from the cyanobacterium Lyngbya majuscula found in the bed of the coral reef. Although KT suppresses cell division and inflammation, KT's mechanism of action in vascular smooth muscle cells (VSMCs) is unidentified. Therefore, our main aim was to investigate the impact of KT on vascular calcification for the treatment of cardiovascular disease. OBJECTIVES Using diverse calcification media, we studied the effect of KT on VSMC calcification and the underlying mechanism of this effect. METHODS VSMC was isolated from the 6 weeks ICR mice. Then VSMCs were treated with different concentrations of KT to check the cell viability. Alizarin red and von Kossa staining were carried out to examine the calcium deposition on VSMC. Thoracic aorta of 6 weeks mice were taken and treated with different concentrations of KT, and H and E staining was performed. Real-time polymerase chain reaction and western blot were performed to examine KT's effect on VSMC mineralization. Calcium deposition on VSMC was examined with a calcium deposition quantification kit. RESULTS Calcium deposition, Alizarin red, and von Kossa staining revealed that KT reduced inorganic phosphate-induced calcification phenotypes. KT also reduced Ca++-induced calcification by inhibiting genes that regulate osteoblast differentiation, such as runt-related transcription factor 2 (RUNX-2), SMAD family member 4, osterix, collagen 1α, and osteopontin. Also, KT repressed Ca2+-induced bone morphogenetic protein 2, RUNX-2, collagen 1α, osteoprotegerin, and smooth muscle actin protein expression. Likewise, Alizarin red and von Kossa staining showed that KT markedly decreased the calcification of ex vivo ring formation in the mouse thoracic aorta. CONCLUSIONS This experiment demonstrated that KT decreases vascular calcification and may be developed as a new therapeutic treatment for vascular calcification and arteriosclerosis.
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Affiliation(s)
- Saroj K Shrestha
- Laboratory of Pharmacology, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Korea
| | - Se-Woong Kim
- Laboratory of Pharmacology, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Korea
| | - Yunjo Soh
- Laboratory of Pharmacology, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Korea.
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10
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Yang Y, Huang Y. Association between bone mineral density and cardiovascular disease in older adults. Front Public Health 2023; 11:1103403. [PMID: 37427263 PMCID: PMC10328748 DOI: 10.3389/fpubh.2023.1103403] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 05/12/2023] [Indexed: 07/11/2023] Open
Abstract
Background and aims Cardiovascular disease and osteoporosis are common diseases in older adults with high morbidity. The study on the interaction between the two in pathogenic mechanisms has been paid much attention by the majority of researchers. This study aimed to explore the relationship between bone mineral density and cardiovascular disease in older adults. Methods The primary data was downloaded from the National Health and Nutrition Examination Survey database of the United States. Multivariate logistic regression model, generalized additive model, and smooth curve fitting were used to explore the relationship between bone mineral density and cardiovascular events risk. When a curve relationship was found, a two-piecewise linear model was used to calculate the inflection point. In addition, subgroup analysis was also performed. Results A total of 2097 subjects were included in this study. After adjusting for potential confounders, no significant association was found between lumbar bone mineral density and cardiovascular disease, while femur bone mineral density had a non-linear relationship with cardiovascular disease, with an inflection point of 0.741 gm/cm2. When bone mineral density was <0.741 gm/cm2, the risk of cardiovascular disease decreased speedily. Once bone mineral density exceeded this value, the risk of cardiovascular disease continued to decrease, but the trend became significantly slower. Compared with patients with normal bone mass, osteoporosis was associated with a 2.05-fold increased risk of cardiovascular disease (95% CI 1.68-5.52). There were no significant differences in interaction tests of all subgroups (p for interaction >0.05) except race. Conclusion Our results indicated that bone mineral density was closely associated with the prevalence of cardiovascular disease in older adults over 60 years old, especially the femur bone mineral density was negatively non-linear associated with cardiovascular disease risk, with an inflection point of 0.741 gm/cm2.
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11
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Böttner J, Werner S, Feistner L, Fischer-Schaepmann T, Neussl K, Borger MA, Thiele H, Büttner P, Schlotter F. High resolution monitoring of valvular interstitial cell driven pathomechanisms in procalcific environment using label-free impedance spectroscopy. Front Cardiovasc Med 2023; 10:1155371. [PMID: 37408660 PMCID: PMC10319251 DOI: 10.3389/fcvm.2023.1155371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Introduction Fibro-calcific aortic valve disease has high prevalence and is associated with significant mortality. Fibrotic extracellular matrix (ECM) remodeling and calcific mineral deposition change the valvular microarchitecture and deteriorate valvular function. Valvular interstitial cells (VICs) in profibrotic or procalcifying environment are frequently used in vitro models. However, remodeling processes take several days to weeks to develop, even in vitro. Continuous monitoring by real-time impedance spectroscopy (EIS) may reveal new insights into this process. Methods VIC-driven ECM remodeling stimulated by procalcifying (PM) or profibrotic medium (FM) was monitored by label-free EIS. Collagen secretion, matrix mineralization, viability, mitochondrial damage, myofibroblastic gene expression and cytoskeletal alterations were analyzed. Results and Discussion EIS profiles of VICs in control medium (CM) and FM were comparable. PM reproducibly induced a specific, biphasic EIS profile. Phase 1 showed an initial impedance drop, which moderately correlated with decreasing collagen secretion (r = 0.67, p = 0.22), accompanied by mitochondrial membrane hyperpolarization and cell death. Phase 2 EIS signal increase was positively correlated with augmented ECM mineralization (r = 0.97, p = 0.008). VICs in PM decreased myofibroblastic gene expression (p < 0.001) and stress fiber assembly compared to CM. EIS revealed sex-specific differences. Male VICs showed higher proliferation and in PM EIS decrease in phase 1 was significantly pronounced compared to female VICs (male minimum: 7.4 ± 4.2%, female minimum: 26.5 ± 4.4%, p < 0.01). VICs in PM reproduced disease characteristics in vitro remarkably fast with significant impact of donor sex. PM suppressed myofibroblastogenesis and favored ECM mineralization. In summary, EIS represents an efficient, easy-to-use, high-content screening tool enabling patient-specific, subgroup- and temporal resolution.
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Affiliation(s)
- Julia Böttner
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | - Sarah Werner
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | - Lukas Feistner
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | | | - Katherina Neussl
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | - Michael A. Borger
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | - Holger Thiele
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | - Petra Büttner
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
| | - Florian Schlotter
- Department of Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig, Germany
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12
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Sun HL, Ma QY, Bian HG, Meng XM, Jin J. Novel insight on GRP/GRPR axis in diseases. Biomed Pharmacother 2023; 161:114497. [PMID: 36933382 DOI: 10.1016/j.biopha.2023.114497] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/26/2023] [Accepted: 03/07/2023] [Indexed: 03/18/2023] Open
Abstract
The gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptors (GPCRs), binds to ligands such as gastrin-releasing peptide (GRP) and plays a variety of biological roles. GRP/GRPR signalling is involved in the pathophysiological processes of many diseases, including inflammatory diseases, cardiovascular diseases, neurological diseases, and various cancers. In the immune system, the unique function of GRP/GRPR in neutrophil chemotaxis suggests that GRPR can be directly stimulated through GRP-mediated neutrophils to activate selective signalling pathways, such as PI3K, PKC, and MAPK, and participate in the occurrence and development of inflammation-related diseases. In the cardiovascular system, GRP increases intercellular adhesion molecule 1 (ICAM-1) and induces vascular cell adhesion molecule-1 (VCAM-1). GRP activates ERK1/2, MAPK, and AKT, leading to cardiovascular diseases, including myocardial infarction. Central nervous system signal transduction mediated by the GRP/GRPR axis plays a vital role in emotional responses, social interaction, and memory. The GRP/GRPR axis is elevated in various cancers, including lung, cervical, colorectal, renal cell, and head and neck squamous cell carcinomas. GRP is a mitogen in a variety of tumour cell lines. Its precursor, pro-gastrin-releasing peptide (ProGRP), may play an important role as an emerging tumour marker in early tumour diagnosis. GPCRs serve as therapeutic targets for drug development, but their function in each disease remains unclear, and their involvement in disease progression has not been well explored or summarised. This review lays out the above mentioned pathophysiological processes based on previous research conclusions. The GRP/GRPR axis may be a potential target for treating multiple diseases, and the study of this signalling axis is particularly important.
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Affiliation(s)
- Hao-Lu Sun
- School of Basic Medical Sciences, Anhui Medical University, Anhui, China
| | - Qiu-Ying Ma
- Department of pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, No. 100 Huaihai Road, Hefei, Anhui, 230012, China
| | - He-Ge Bian
- School of Basic Medical Sciences, Anhui Medical University, Anhui, China
| | - Xiao-Ming Meng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei 230032, China.
| | - Juan Jin
- School of Basic Medical Sciences, Anhui Medical University, Anhui, China.
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Kim TI, Guzman RJ. Medial artery calcification in peripheral artery disease. Front Cardiovasc Med 2023; 10:1093355. [PMID: 36776265 PMCID: PMC9909396 DOI: 10.3389/fcvm.2023.1093355] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/13/2023] [Indexed: 01/28/2023] Open
Abstract
Medial artery calcification (MAC) is a distinct, highly regulated process that is often identified in small and mid-sized arteries of the lower extremities. It is associated with advanced age, diabetes, and chronic kidney disease. MAC often occurs in conjunction with atherosclerotic occlusive disease in lower extremity arteries, and when seen together or in isolation, long-term limb outcomes are negatively affected. In patients with peripheral artery disease (PAD), the extent of MAC independently correlates with major amputation and mortality rates, and it predicts poor outcomes after endovascular interventions. It is associated with increased arterial stiffness and decreased pedal perfusion. New endovascular methods aimed at treating calcified lower-extremity lesions may improve our ability to treat patients with limb-threatening ischemia. Although recent developments have increased our understanding of the mechanisms contributing to MAC, further investigations are needed to understand the role of medial calcification in PAD, and to develop strategies aimed at improving patient outcomes.
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Affiliation(s)
- Tanner I. Kim
- Deparment of Surgery, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States
- The Queen’s Health Systems, Honolulu, HI, United States
| | - Raul J. Guzman
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale School of Medicine, New Haven, CT, United States
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Liu YH, Liu Y, Xin YF, Zhang Q, Ding ML. Identification of key genes involved in calcific aortic valve disease based on integrated bioinformatics analysis. Exp Biol Med (Maywood) 2023; 248:52-60. [PMID: 36151748 PMCID: PMC9989152 DOI: 10.1177/15353702221118088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The calcific aortic valve disease (CAVD) develops as an aortic valve sclerosis and progresses to an advanced form of stenosis. In many biological fields, bioinformatics becomes a fundamental component. The key mechanisms involved in CAVD are discovered with the use of bioinformatics to investigate gene function and pathways. We downloaded the original data (GSE51472) from the Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/). After standardization, 2978 differentially expressed genes (DEGs) were identified from the data sets GSE51472 containing samples from normal, calcified, and sclerotic aortic valves. Analysis of DEGs based on the series test of clusters (STCs) revealed the two most significant patterns. Based on the result of the STC, the functional enrichment analysis of gene ontology (GO) was conducted to investigate the molecular function (MF), biological process (BP), and cell compound (CC) of the DEGs. With a p value of 0.01, DEGs associated with "chronic inflammation," "T-cell receptor complexes," and "antigen binding" had the highest significance within BP, CC, and MF. DEG enrichment in signaling pathways was analyzed using KEGG pathway enrichment. Using a p < 0.05 level of significance, the most enriched biological pathways related to CAVD were "Chemokine signaling pathway," "Cytokine-cytokine receptor interaction," "Tuberculosis," "PI3K-Akt signaling pathway," and "Transcriptional misregulation in cancer." Finally, the construction of gene co-expression networks and pathway networks illustrated the pathogensis of CAVD. TLR2, CD86, and TYROBP were identified as hub genes for the development of CAVD. Moreover, "MAPK signaling pathway," "Apoptosis," and "Pathways in cancer" were regarded as the core pathways among the samples of normal, sclerotic and calcified aortic valve samples.
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Affiliation(s)
- Ye-Hong Liu
- Department of Cardiology, Shanghai East Hospital, Shanghai Tongji University School of Medicine, Shanghai 200120, China
| | - Yang Liu
- Department of Intensive Care Unit, Shanghai East Hospital, Shanghai Tongji University School of Medicine, Shanghai 200120, China
| | - Yuan-Feng Xin
- Department of Cardiovascular Surgery, Shanghai East Hospital, Shanghai Tongji University School of Medicine, Shanghai 200120, China
| | - Qi Zhang
- Department of Cardiology, Shanghai East Hospital, Shanghai Tongji University School of Medicine, Shanghai 200120, China
| | - Meng-Lei Ding
- Department of Clinical Laboratory, Shanghai East Hospital, Shanghai Tongji University School of Medicine, Shanghai 200120, China
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15
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Mo L, Ma C, Wang Z, Li J, He W, Niu W, Chen Z, Zhou C, Liu Y. Integrated Bioinformatic Analysis of the Shared Molecular Mechanisms Between Osteoporosis and Atherosclerosis. Front Endocrinol (Lausanne) 2022; 13:950030. [PMID: 35937806 PMCID: PMC9353191 DOI: 10.3389/fendo.2022.950030] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 06/22/2022] [Indexed: 11/30/2022] Open
Abstract
Background Osteoporosis and atherosclerosis are common in the elderly population, conferring a heavy worldwide burden. Evidence links osteoporosis and atherosclerosis but the exact underlying common mechanism of its occurrence is unclear. The purpose of this study is to further explore the molecular mechanism between osteoporosis and atherosclerosis through integrated bioinformatic analysis. Methods The microarray data of osteoporosis and atherosclerosis in the Gene Expression Omnibus (GEO) database were downloaded. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the co-expression genes related to osteoporosis and atherosclerosis. In addition, the common gene targets of osteoporosis and atherosclerosis were analyzed and screened through three public databases (CTD, DISEASES, and GeneCards). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape. Then, the common microRNAs (miRNAs) in osteoporosis and atherosclerosis were screened out from the Human microRNA Disease Database (HMDD) and the target genes of whom were predicted through the miRTarbase. Finally, the common miRNAs-genes network was constructed by Cytoscape software. Results The results of common genes analysis showed that immune and inflammatory response may be a common feature in the pathophysiology of osteoporosis and atherosclerosis. Six hub genes (namely, COL1A1, IBSP, CTSD, RAC2, MAF, and THBS1) were obtained via taking interaction of different analysis results. The miRNAs-genes network showed that has-let-7g might play an important role in the common mechanisms between osteoporosis and atherosclerosis. Conclusion This study provides new sights into shared molecular mechanisms between osteoporosis and atherosclerosis. These common pathways and hub genes may offer promising clues for further experimental studies.
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Affiliation(s)
- Liang Mo
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chao Ma
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhangzheng Wang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jianxiong Li
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Wei He
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, Guangzhou, China
| | - Wei Niu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhengqiu Chen
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chi Zhou
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuhao Liu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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16
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Yokouchi Y, Oharaseki T, Asakawa N, Makino H, Takahashi K. Histological studies shed new light on the initiation and characteristics of calcification of coronary artery aneurysms in Kawasaki disease. Cardiovasc Pathol 2022; 61:107456. [PMID: 35868495 DOI: 10.1016/j.carpath.2022.107456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 06/27/2022] [Accepted: 07/13/2022] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND Calcification of coronary artery aneurysms (CAAs) is common in the remote phase of Kawasaki disease (KD), but the detailed features of its development remain unclear. This study aimed to elucidate the histological characteristics of calcification in KD CAAs. MATERIALS AND METHODS The study materials consisted of 24 coronary artery branches with aneurysms that were obtained from 14 Japanese patients who died during the period from 40 days to 3 years after the onset of KD. We first examined the CAAs for the presence of thrombi and calcification. When calcifications were observed, we determined their location and shape, and investigated the time-course of the changes based on the time-interval from KD onset until death. Then we measured the area of each calcification and examined for correlations between the calcified area and (1) the disease duration and (2) the aneurysm diameter. RESULTS Calcification was observed in 14 of the 24 CAAs (in 7 of 13 LCA and 7 of 11 RCA). Thrombi were also seen in 13 of the 14 CAAs with calcification. Calcification showed two localizations: in the organized portion of the thrombus (seen in 12 CAAs) and deep in the thickened tunica of the intima (3 CAAs). The earliest observation of calcification was in an infant who died on the 49th disease day: it was a small, band-shaped calcified lesion in granulation tissue that had formed at the boundary between the thrombus and the blood vessel wall. As the duration of KD increased, the calcified lesion increased in size, and nodular shapes were formed. Moreover, the calcified area tended to increase as the diameter of the aneurysm increased. CONCLUSION Histologically, CAA calcification starts early in the remote phase of KD, and it is closely related to organization of thrombi.
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Affiliation(s)
- Yuki Yokouchi
- Department of Surgical Pathology, Toho University Ohashi Medical Center, Tokyo, Japan.
| | - Toshiaki Oharaseki
- Department of Surgical Pathology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Nanae Asakawa
- Department of Surgical Pathology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Haruki Makino
- Department of Surgical Pathology, Toho University Ohashi Medical Center, Tokyo, Japan
| | - Kei Takahashi
- Department of Surgical Pathology, Toho University Ohashi Medical Center, Tokyo, Japan
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Nguyen TT, Hu CC, Sakthivel R, Nabilla SC, Huang YW, Yu J, Cheng NC, Kuo YJ, Chung RJ. Preparation of gamma poly-glutamic acid/hydroxyapatite/collagen composite as the 3D-printing scaffold for bone tissue engineering. Biomater Res 2022; 26:21. [PMID: 35642070 PMCID: PMC9158383 DOI: 10.1186/s40824-022-00265-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 05/02/2022] [Indexed: 11/19/2022] Open
Abstract
Background All types of movements involve the role of articular cartilage and bones. The presence of cartilage enables bones to move over one another smoothly. However, repetitive microtrauma and ischemia as well as genetic effects can cause an osteochondral lesion. Numerous treatment methods such as microfracture surgergy, autograft, and allograft, have been used, however, it possesses treatment challenges including prolonged recovery time after surgery and poses a financial burden on patients. Nowadays, various tissue engineering approaches have been developed to repair bone and osteochondral defects using biomaterial implants to induce the regeneration of stem cells. Methods In this study, a collagen (Col)/γ-polyglutamate acid (PGA)/hydroxyapatite (HA) composite scaffold was fabricated using a 3D printing technique. A Col/γ-PGA/HA 2D membrane was also fabricated for comparison. The scaffolds (four layers) were designed with the size of 8 mm in diameter and 1.2 mm in thickness. The first layer was HA/γ-PGA and the second to fourth layers were Col/γ-PGA. In addition, a 2D membrane was constructed from hydroxyapatite/γ-PGA and collagen/γ-PGA with a ratio of 1:3. The biocompatibility property and degradation activity were investigated for both scaffold and membrane samples. Rat bone marrow mesenchymal stem cells (rBMSCs) and human adipose-derived stem cells (hADSCs) were cultured on the samples and were tested in-vitro to evaluate cell attachment, proliferation, and differentiation. In-vivo experiments were performed in the rat and nude mice models. Results In-vitro and in-vivo results show that the developed scaffold is of well biodegradation and biocompatible properties, and the Col-HA scaffold enhances the mechanical properties for osteochondrogenesis in both in-vitro and animal trials. Conclusions The composite would be a great biomaterial application for bone and osteochondral regeneration.
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Subcutaneous Calcifications in Legs with Chronic Venous Diseases. J Vasc Surg Venous Lymphat Disord 2022; 10:689-696. [PMID: 35217216 DOI: 10.1016/j.jvsv.2022.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/05/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Calcifications in the subcutaneous layer (SCL) have been described by x-rays studies in legs with advanced chronic venous disorders (CVD). However, SCL calcifications are rarely included among the changes CVD-related. The aim of this study was to evaluate the prevalence and morphology of SCL calcifications in legs with CVD of all grades of severity by ultrasonography (US). MATERIAL AND METHODS Five hundred legs in 250 patients (148 females and 102 males, mean age 51, range 18-87) referred to the vascular clinic for symptoms and signs of CVD were included. After the Duplex evaluation of deep, superficial, and perforating veins the skin and the SCL were investigated by Duplex sonography. Subjects with other possible cause of SCL calcification were excluded. RESULTS According to the CEAP-C classification, 43 legs were classified as C1,189 as C2, 34 as C3, 16 as C4A, 45 as C4B or C, 18 as C5 and finally 16 as C6. Varicose veins were reported in 273 legs, lipodermatosclerosis (LDS) in 79. Subcutaneous calcifications were demonstrated in 35/361 CVD legs in two different locations: in the wall of superficial varicose veins (SVC) or in the subcutaneous tissue unrelated to the path of superficial veins (STC). The SVC were found in 12 out of 273 legs with varicose veins (4.4%). They were found in older patients with severe varicose veins disease (grade 3 of VCSS and disease duration >30 yrs). The STC were found in 24 out of 95 legs in the more advanced CVD stages (C4A-C6 classes). No STC were found in C1, C2, and C3 legs. DISCUSSION SVC were found only in legs with severe and long-lasting varicose veins and seem to be related to a chronic severe inflammation of the venous wall. STC are independent from the vein wall and were found only in the damaged areas of legs with severe CVD (C4-C6). They are possibly related to chronic inflammation of the subcutaneous tissue. Their avulsion from the ulcer bed is recommended to facilitate ulcer healing and prevent their recurrence.
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Chen Q, Yao Y, Chen K, Chen X, Li B, Li R, Mo L, Hu W, Zhang M, Wang Z, Wu Y, Wu Y, Liu F. Aberrant activation of TGF-β1 induces high bone turnover via Rho GTPases-mediated cytoskeletal remodeling in Camurati-Engelmann disease. Front Endocrinol (Lausanne) 2022; 13:913979. [PMID: 36325441 PMCID: PMC9621586 DOI: 10.3389/fendo.2022.913979] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 09/28/2022] [Indexed: 11/24/2022] Open
Abstract
In the adult skeleton, the bone remodeling process involves a dynamic coordination between osteoblasts and osteoclasts, which is disrupted in diseases with high bone turnover rates and dysregulated transforming growth factor beta 1 (TGF-β1). However, little is known about how TGF-β1 signaling mediates bone resorption. Here, we described a pedigree with a heterozygous variant in TGF-β1 (R218C) that resulted in aberrant activation of TGF-β1 through an activating mechanism that caused Camurati-Engelmann disease (CED). We showed that CED patients have high levels of active Rho GTPases and the migration-related proteins Integrin β1 and Integrin β3 in their peripheral blood. HEK293T cells transfected with a plasmid encoding this mutant expressed high levels of TGF-β1 and active Rho GTPases. Furthermore, activation of Rho by TGF-β1 increased osteoclast formation and bone resorption, with increased migration of pre-osteoclasts, as well as cytoskeletal remodeling of pre-osteoclasts and mature osteoclasts. Importantly, pharmacological inhibition of Rho GTPases effectively rescued hyperactive TGF-β1-induced osteoclastogenesis in vitro. Overall, we propose that Rho GTPases mediate TGF-β1-induced osteoclastogenesis and suggest that Rho-TGF-β1 crosstalk is associated with high bone turnover in CED.
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Affiliation(s)
- Qi Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Clinic Genetics, Air Force Medical University, Xi’an, China
| | - Yan Yao
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Department of Cell Biology and Genetics, Medical College of Yan'an University, Yan’an, China
| | - Kun Chen
- Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, School of Basic Medicine, Air Force Medical University, Xi’an, China
| | - Xihui Chen
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Clinic Genetics, Air Force Medical University, Xi’an, China
| | - Bowen Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Clinic Genetics, Air Force Medical University, Xi’an, China
| | - Rui Li
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Clinic Genetics, Air Force Medical University, Xi’an, China
| | - Lidangzhi Mo
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Clinic Genetics, Air Force Medical University, Xi’an, China
| | - Weihong Hu
- Department of Cell Biology and Genetics, Medical College of Yan'an University, Yan’an, China
| | - Mengjie Zhang
- Department of Cell Biology and Genetics, Medical College of Yan'an University, Yan’an, China
| | - Zhen Wang
- Department of Orthopedics, The First Affiliated Hospital of Air Force Medical University, Xi’an, China
| | - Yaoping Wu
- Department of Orthopedics, The First Affiliated Hospital of Air Force Medical University, Xi’an, China
- *Correspondence: Fangfang Liu, ; Yuanming Wu, ; Yaoping Wu,
| | - Yuanming Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- Shaanxi Provincial Key Laboratory of Clinic Genetics, Air Force Medical University, Xi’an, China
- *Correspondence: Fangfang Liu, ; Yuanming Wu, ; Yaoping Wu,
| | - Fangfang Liu
- Department of Neurobiology, School of Basic Medicine, Air Force Medical University, Xi’an, China
- *Correspondence: Fangfang Liu, ; Yuanming Wu, ; Yaoping Wu,
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20
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Zheng R, Zhu P, Gu J, Ni B, Sun H, He K, Bian J, Shao Y, Du J. Transcription factor Sp2 promotes TGFB-mediated interstitial cell osteogenic differentiation in bicuspid aortic valves through a SMAD-dependent pathway. Exp Cell Res 2021; 411:112972. [PMID: 34914964 DOI: 10.1016/j.yexcr.2021.112972] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 12/04/2021] [Accepted: 12/10/2021] [Indexed: 11/04/2022]
Abstract
Calcification of the bicuspid aortic valve (BAV) involves differential expression of various RNA genes, which is achieved through complex regulatory networks that are controlled in part by transcription factors and microRNAs. We previously found that miR-195-5p regulates the osteogenic differentiation of valvular interstitial cells (VICs) by targeting the TGF-β pathway. However, the transcriptional regulation of miR-195-5p in calcified BAV patients is not yet clear. In this study, stenotic aortic valve tissues from patients with BAVs and tricuspid aortic valves (TAVs) were collected. Candidate transcription factors of miR-195-5p were predicted by bioinformatics analysis and tested in diseased valves and in male porcine VICs. SP2 gene expression and the corresponding protein levels in BAV were significantly lower than those in TAV, and a low SP2 expression level environment in VICs resulted in remarkable increases in RNA expression levels of RUNX2, BMP2, collagen 1, MMP2, and MMP9 and the corresponding proteins. ChIP assays revealed that SP2 directly bound to the transcription promoter region of miR-195-5p. Cotransfection of SP2 shRNA and a miR-195-5p mimic in porcine VICs demonstrated that SP2 repressed SMAD7 expression via miR-195-5p, while knockdown of SP2 increased the mRNA expression of SMAD7 and the corresponding protein and attenuated Smad 2/3 expression. Immunofluorescence staining of diseased valves confirmed that the functional proteins of osteogenesis differentiation, including RUNX2, BMP2, collagen 1, and osteocalcin, were overexpressed in BAVs. In Conclusion, the transcription factor Sp2 is expressed at low levels in VICs from BAV patients, which has a negative impact on miR-195-5p expression by binding its promoter region and partially promotes calcification through a SMAD-dependent pathway.
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Affiliation(s)
- Rui Zheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Pengcheng Zhu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Jiaxi Gu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Buqing Ni
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Haoliang Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Keshuai He
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Jinhui Bian
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China
| | - Yongfeng Shao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China.
| | - Junjie Du
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, PR China.
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21
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Santhanam L, Liu G, Jandu S, Su W, Wodu BP, Savage W, Poe A, Liu X, Alexander LM, Cao X, Wan M. Skeleton-secreted PDGF-BB mediates arterial stiffening. J Clin Invest 2021; 131:e147116. [PMID: 34437300 PMCID: PMC8516464 DOI: 10.1172/jci147116] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.
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Affiliation(s)
- Lakshmi Santhanam
- Department of Anesthesiology and Critical Care Medicine and
- Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Guanqiao Liu
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Sandeep Jandu
- Department of Anesthesiology and Critical Care Medicine and
| | - Weiping Su
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Orthopaedic Surgery, The Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Bulouere P. Wodu
- Department of Biotechnology, The Johns Hopkins University, Baltimore, Maryland, USA
| | - William Savage
- Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, The Johns Hopkins University, Baltimore, Maryland, USA
| | - Alan Poe
- Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Xiaonan Liu
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lacy M. Alexander
- Department of Kinesiology, Penn State University, University Park, Pennsylvania, USA
| | - Xu Cao
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mei Wan
- Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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22
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Zaidi M, Lizneva D, Yuen T. The role of PDGF-BB in the bone-vascular relationship during aging. J Clin Invest 2021; 131:153644. [PMID: 34651590 DOI: 10.1172/jci153644] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cardiovascular disease (CVD) and osteoporosis often occur together, suggesting an association between CVD and bone loss. Similarly, the correlation of bone loss, atherosclerosis, and aortic calcification, especially in patients with chronic kidney disease, exemplifies a bone-vessel connection. In this issue of the JCI, Santhanam et al. investigated the role of the angiogenesis factor platelet-derived growth factor-BB (PDGF-BB) in vascular stiffening. Serum levels of bone-derived PDGF-BB differed between young and aged mice, and in mice fed a high-fat diet (HFD) compared with those fed normal chow. Experiments with genetic models led the authors to conclude that bone-derived PDGF-BB mediates the hallmark arterial stiffening of aging and metabolic stress. Notably, excessive preosteoclast-derived PDGF-BB production during aging inhibited osteoblastic bone formation and increased circulating PDGF-BB, which in turn, accelerated vascular stiffness. These findings suggest that modifying circulating PDGF-BB levels may benefit patients with CVD, osteoporosis, and other age-related diseases.
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Affiliation(s)
- Mone Zaidi
- Department of Medicine.,Department of Pharmacological Sciences, and.,Center of Excellence for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Daria Lizneva
- Department of Medicine.,Department of Pharmacological Sciences, and.,Center of Excellence for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Tony Yuen
- Department of Medicine.,Department of Pharmacological Sciences, and.,Center of Excellence for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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23
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Li M, Zhu Y, Jaiswal SK, Liu NF. Mitochondria Homeostasis and Vascular Medial Calcification. Calcif Tissue Int 2021; 109:113-120. [PMID: 33660037 DOI: 10.1007/s00223-021-00828-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 02/18/2021] [Indexed: 12/25/2022]
Abstract
Vascular calcification occurs highly prevalent, which commonly predicts adverse cardiovascular events. The pathogenesis of calcification, a complicated and multifactorial process, is incompletely characterized. Accumulating evidence shows that mitochondrial dysfunction may ultimately be more detrimental in the vascular smooth muscle cells (VSMCs) calcification. This review summarizes the role of mitochondrial dysfunction and metabolic reprogramming in vascular calcification, and indicates that metabolic regulation may be a therapeutic target in vascular calcification.
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Affiliation(s)
- Min Li
- Department of Cardiology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, People's Republic of China
| | - Yi Zhu
- Department of Cardiology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, People's Republic of China
| | - Sandip Kumar Jaiswal
- Department of Neurology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, People's Republic of China
| | - Nai-Feng Liu
- Department of Cardiology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, People's Republic of China.
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24
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Liu L, Wang L, Li L, Wang H, Yuan L, Kang L, Jiang Q, Chen G, Lv N, Cui X, Huang L, Wu H, Xu J, Li Y. Effects of triangle grass decoction on bone metabolism in rats with chronic kidney disease complicated with mineral and bone abnormalities. JOURNAL OF ETHNOPHARMACOLOGY 2021; 275:114126. [PMID: 33872749 DOI: 10.1016/j.jep.2021.114126] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/08/2021] [Accepted: 04/13/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Triangle grass is a liliaceous Chlorophytum perennial herb of ChlorophytumlaxumR.Br. It is distributed mainly in Guangdong and Guangxi Provinces of China. The initial use of triangle grass was mainly to treat bone pain and swelling caused by a fall injury. Triangle grass tablets (NO. Z20070544) are also used as a preparation in our hospital because of their analgesic, anti-inflammatory, anti-snake venom and microcirculation improvement properties and other pharmacological effects (Mei et al., 2006). Triangle grass tablets have been widely used in our hospital to treat patients with bone pain from chronic kidney disease-mineral and bone disorder (CKD-MBD). However, the effects and mechanism of triangle grass on bone metabolism in chronic kidney disease complicated with mineral and bone abnormalities are unclear. AIM OF THE STUDY The aim of the present study was to investigate the effects of a triangle grass decoction on bone metabolism in CKD-MBD rats. MATERIALS AND METHODS CKD-MBD model rats were subjected to 5/6 nephrectomy combined with 0.5 g NaH2PO4/rat. Serum blood urea nitrogen (BUN), creatinine (Cr), phosphorus (P), calcium (Ca), and intact parathyroid hormone (iPTH) levels were measured with an automatic biochemical analyser. Bone mineral density was determined with a Viva CT 40 system. Bone morphogenetic protein 7(BMP-7),runt-related transcription factor 2 (Runx2) and Osterix protein levels were measured by Western blot analysis. Kidney, vertebra and thoracic aorta tissue samples were assessed by histopathology and immunohistochemistry (IHC). RESULTS The degrees of membrane thickening, necrosis, swelling and cast deposition were significantly reduced in high-dose rats and Low-dose rats. Serum BUN levels were significantly reduced in the Pre-H group (P < 0.05). Hypocalcaemia and hyperphos phataemia were detected in triangle grass (P < 0.05, P < 0.05). In addition, iPTH levels were significantly increased in the Pre-H group (P < 0.05). Alkaline phosphatase (ALP)levels were significantly decreased in the Pre-H group (P < 0.05). The bone mineral density was improved in the Pre-H and Pre-L groups. BMP-7 protein levels were significantly increased in the Pre-H group (P < 0.05). The pathological changes in muscle fibres in the thoracic aorta middle membranes were significantly alleviated in rats in the Pre-H and Pre-L groups. Changes in SM22α and SMα-act in protein levels were significantly attenuated in the Pre-H group (P < 0.05, P < 0.05). Changes in Runx2 and Osterix protein levels were also significantly attenuated in the Pre-H and Pre-L groups (P < 0.05, P < 0.05). CONCLUSIONS Triangle grass can simultaneously ameliorate vertebral bone loss and abnormal calcification in the thoracic aorta. Triangle grass has a definite effect on bone metabolism disorder in CKD-MBD rats.
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Affiliation(s)
- Linna Liu
- Department of Nephrology, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, 528400, China.
| | - Lei Wang
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Li Li
- Second Clinical College of Traditional Chinese Medicine, University of Guangzhou, Guangzhou, 510405, China.
| | - Hong Wang
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Ling Yuan
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Li Kang
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Qian Jiang
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Guan Chen
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Nan Lv
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Xiaoxue Cui
- Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin, 300020, China.
| | - Lin Huang
- Department of Nephrology, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, 528400, China.
| | - Huifei Wu
- Department of Nephrology, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, 528400, China.
| | - Juan Xu
- Department of Nephrology, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, 528400, China.
| | - Yanlin Li
- Department of Nephrology, Zhongshan Hospital of Traditional Chinese Medicine, Zhongshan, 528400, China.
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25
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Su H, Cantrell AC, Zeng H, Zhu SH, Chen JX. Emerging Role of Pericytes and Their Secretome in the Heart. Cells 2021; 10:548. [PMID: 33806335 PMCID: PMC8001346 DOI: 10.3390/cells10030548] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/25/2021] [Accepted: 02/27/2021] [Indexed: 12/11/2022] Open
Abstract
Pericytes, as mural cells covering microvascular capillaries, play an essential role in vascular remodeling and maintaining vascular functions and blood flow. Pericytes are crucial participants in the physiological and pathological processes of cardiovascular disease. They actively interact with endothelial cells, vascular smooth muscle cells (VSMCs), fibroblasts, and other cells via the mechanisms involved in the secretome. The secretome of pericytes, along with diverse molecules including proinflammatory cytokines, angiogenic growth factors, and the extracellular matrix (ECM), has great impacts on the formation, stabilization, and remodeling of vasculature, as well as on regenerative processes. Emerging evidence also indicates that pericytes work as mesenchymal cells or progenitor cells in cardiovascular regeneration. Their capacity for differentiation also contributes to vascular remodeling in different ways. Previous studies primarily focused on the roles of pericytes in organs such as the brain, retina, lung, and kidney; very few studies have focused on pericytes in the heart. In this review, following a brief introduction of the origin and fundamental characteristics of pericytes, we focus on pericyte functions and mechanisms with respect to heart disease, ending with the promising use of cardiac pericytes in the treatment of ischemic heart failure.
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Affiliation(s)
- Han Su
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Aubrey C Cantrell
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Heng Zeng
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Shai-Hong Zhu
- Department of General Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Jian-Xiong Chen
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
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26
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Boraldi F, Lofaro FD, Quaglino D. Apoptosis in the Extraosseous Calcification Process. Cells 2021; 10:cells10010131. [PMID: 33445441 PMCID: PMC7827519 DOI: 10.3390/cells10010131] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/07/2021] [Accepted: 01/10/2021] [Indexed: 12/13/2022] Open
Abstract
Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries.
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Affiliation(s)
- Federica Boraldi
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.D.L.); (D.Q.)
- Correspondence:
| | - Francesco Demetrio Lofaro
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.D.L.); (D.Q.)
| | - Daniela Quaglino
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (F.D.L.); (D.Q.)
- Interuniversity Consortium for Biotechnologies (CIB), Italy
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27
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Chen Y, Zhao X, Wu H. Transcriptional Programming in Arteriosclerotic Disease: A Multifaceted Function of the Runx2 (Runt-Related Transcription Factor 2). Arterioscler Thromb Vasc Biol 2021; 41:20-34. [PMID: 33115268 PMCID: PMC7770073 DOI: 10.1161/atvbaha.120.313791] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Despite successful therapeutic strategies in the prevention and treatment of arteriosclerosis, the cardiovascular complications remain a major clinical and societal issue worldwide. Increased vascular calcification promotes arterial stiffness and accelerates cardiovascular morbidity and mortality. Upregulation of the Runx2 (Runt-related transcription factor 2), an essential osteogenic transcription factor for bone formation, in the cardiovascular system has emerged as an important regulator for adverse cellular events that drive cardiovascular pathology. This review discusses the regulatory mechanisms that are critical for Runx2 expression and function and highlights the dynamic and complex cross talks of a wide variety of posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and O-linked β-N-acetylglucosamine modification, in regulating Runx2 stability, cellular localization, and osteogenic transcriptional activity. How the activation of an array of signaling cascades by circulating and local microenvironmental factors upregulates Runx2 in vascular cells and promotes Runx2-mediated osteogenic transdifferentiation of vascular smooth muscle cells and expression of inflammatory cytokines that accelerate macrophage infiltration and vascular osteoclast formation is summarized. Furthermore, the increasing appreciation of a new role of Runx2 upregulation in promoting vascular smooth muscle cell phenotypic switch, and Runx2 modulated by O-linked β-N-acetylglucosamine modification and Runx2-dependent repression of smooth muscle cell-specific gene expression are discussed. Further exploring the regulation of this key osteogenic transcription factor and its new perspectives in the vasculature will provide novel insights into the transcriptional regulation of vascular smooth muscle cell phenotype switch, reprograming, and vascular inflammation that promote the pathogenesis of arteriosclerosis.
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Affiliation(s)
- Yabing Chen
- Department of Pathology, University of Alabama at Birmingham
- Research Department, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama 35294
| | - Xinyang Zhao
- Department of Biochemistry, University of Alabama at Birmingham
| | - Hui Wu
- Department of Integrative Biomedical & Diagnostic Sciences, Oregon Health and Science University School of Dentistry, Portland, Oregon 97239
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28
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Yang P, Troncone L, Augur ZM, Kim SSJ, McNeil ME, Yu PB. The role of bone morphogenetic protein signaling in vascular calcification. Bone 2020; 141:115542. [PMID: 32736145 PMCID: PMC8185454 DOI: 10.1016/j.bone.2020.115542] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/02/2020] [Accepted: 07/04/2020] [Indexed: 01/10/2023]
Abstract
Vascular calcification is associated with atherosclerosis, chronic kidney disease, and diabetes, and results from processes resembling endochondral or intramembranous ossification, or from processes that are distinct from ossification. Bone morphogenetic proteins (BMP), as well as other ligands, receptors, and regulators of the transforming growth factor beta (TGFβ) family regulate vascular and valvular calcification by modulating the phenotypic plasticity of multipotent progenitor lineages associated with the vasculature or valves. While osteogenic ligands BMP2 and BMP4 appear to be both markers and drivers of vascular calcification, particularly in atherosclerosis, BMP7 may serve to protect against calcification in chronic kidney disease. BMP signaling regulators such as matrix Gla protein and BMP-binding endothelial regulator protein (BMPER) play protective roles in vascular calcification. The effects of BMP signaling molecules in vascular calcification are context-dependent, tissue-dependent, and cell-type specific. Here we review the current knowledge on mechanisms by which BMP signaling regulates vascular calcification and the potential therapeutic implications.
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Affiliation(s)
- Peiran Yang
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Luca Troncone
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Zachary M Augur
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Stephanie S J Kim
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Megan E McNeil
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Paul B Yu
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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29
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Evaluation of the anatomical variations of the coronary venous system in patients with coronary artery calcification using 256-slice computed tomography. PLoS One 2020; 15:e0242216. [PMID: 33206718 PMCID: PMC7673525 DOI: 10.1371/journal.pone.0242216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 10/28/2020] [Indexed: 11/20/2022] Open
Abstract
The factors that determine the anatomical variations of the coronary venous system (CVS) are poorly understood. The objective of this study was to evaluate the anatomical variations of the CVS in patients with coronary artery calcification. 196 patients underwent non-contrast CT and coronary CT angiography using 256-slice CT. All subjects were divided into four groups based on their coronary artery calcium score (CACS): 50 patients with CACS = 0 Agatston unit (AU), 52 patients with CACS = 1–100 AU, 44 patients with CACS = 101–400 AU, and 50 patients with CACS > 400 AU. The presence of the following cardiac veins was evaluated: the coronary sinus (CS), great cardiac vein (GCV), posterior interventricular vein (PIV), posterior vein of the left ventricle (PVLV), left marginal vein (LMV), anterior interventricular vein (AIV), and small cardiac vein (SCV). Vessel diameters were also measured. We found that the CS, GCV, PIV, and AIV were visualized in all patients, whereas the PVLV and LMV were identified in a certain proportion of patients: 98% and 96% in the CACS = 0 AU group, 100% and 78.8% in the CACS = 1–100 AU group, 93.2% and 77.3% in the CACS = 101–400 AU group, and 98% and 78% in the CACS > 400 AU group, respectively. The LMV was less often identified in the last three groups than in the first group (p < 0.05). The frequency of having either one PVLV or LMV was higher in the last three groups than in the first group (p < 0.05). No significant differences in vessel diameters were observed between the groups. It was concluded that patients with coronary artery calcification were less likely to have the LMV, which might hamper the left ventricular lead implantation in cardiac resynchronization therapy.
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30
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Müller KH, Hayward R, Rajan R, Whitehead M, Cobb AM, Ahmad S, Sun M, Goldberga I, Li R, Bashtanova U, Puszkarska AM, Reid DG, Brooks RA, Skepper JN, Bordoloi J, Chow WY, Oschkinat H, Groombridge A, Scherman OA, Harrison JA, Verhulst A, D'Haese PC, Neven E, Needham LM, Lee SF, Shanahan CM, Duer MJ. Poly(ADP-Ribose) Links the DNA Damage Response and Biomineralization. Cell Rep 2020; 27:3124-3138.e13. [PMID: 31189100 PMCID: PMC6581741 DOI: 10.1016/j.celrep.2019.05.038] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 04/03/2019] [Accepted: 05/09/2019] [Indexed: 11/25/2022] Open
Abstract
Biomineralization of the extracellular matrix is an essential, regulated process. Inappropriate mineralization of bone and the vasculature has devastating effects on patient health, yet an integrated understanding of the chemical and cell biological processes that lead to mineral nucleation remains elusive. Here, we report that biomineralization of bone and the vasculature is associated with extracellular poly(ADP-ribose) synthesized by poly(ADP-ribose) polymerases in response to oxidative and/or DNA damage. We use ultrastructural methods to show poly(ADP-ribose) can form both calcified spherical particles, reminiscent of those found in vascular calcification, and biomimetically calcified collagen fibrils similar to bone. Importantly, inhibition of poly(ADP-ribose) biosynthesis in vitro and in vivo inhibits biomineralization, suggesting a therapeutic route for the treatment of vascular calcifications. We conclude that poly(ADP-ribose) plays a central chemical role in both pathological and physiological extracellular matrix calcification.
Poly(ADP-ribose) is found close to ECM calcification in developing bone and arteries Poly(ADP-ribose) is produced in response to oxidative stress and delivered to the ECM Poly(ADP-ribose) forms dense liquid droplets with calcium ions Inhibiting PARP enzyme activity blocks calcification in vitro and in vivo
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Affiliation(s)
- Karin H Müller
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Robert Hayward
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Rakesh Rajan
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Meredith Whitehead
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Andrew M Cobb
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Sadia Ahmad
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Mengxi Sun
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Ieva Goldberga
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Rui Li
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Uliana Bashtanova
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Anna M Puszkarska
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - David G Reid
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Roger A Brooks
- Division of Trauma and Orthopaedic Surgery, University of Cambridge, Box 180, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
| | - Jeremy N Skepper
- Cambridge Advanced Imaging Centre, Department of Physiology, Development and Neurobiology, Downing Site, Tennis Court Road, Cambridge CB2 3DY, UK
| | - Jayanta Bordoloi
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - Wing Ying Chow
- Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) im Forschungsverbund Berlin e.V., Campus Berlin-Buch, Robert-Roessle-Str 10, 13125 Berlin, Germany
| | - Hartmut Oschkinat
- Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) im Forschungsverbund Berlin e.V., Campus Berlin-Buch, Robert-Roessle-Str 10, 13125 Berlin, Germany
| | - Alex Groombridge
- Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Oren A Scherman
- Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - James A Harrison
- Cycle Pharmaceuticals Ltd, Bailey Grundy Barrett Building, Little St. Mary's Lane, Cambridge CB2 1RR, UK
| | - Anja Verhulst
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
| | - Patrick C D'Haese
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
| | - Ellen Neven
- Laboratory of Pathophysiology, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium
| | - Lisa-Maria Needham
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Steven F Lee
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
| | - Catherine M Shanahan
- BHF Centre of Research Excellence, Cardiovascular Division, James Black Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK.
| | - Melinda J Duer
- Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
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Saito Y, Nakamura K, Ito H. Effects of Eicosapentaenoic Acid on Arterial Calcification. Int J Mol Sci 2020; 21:ijms21155455. [PMID: 32751754 PMCID: PMC7432365 DOI: 10.3390/ijms21155455] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/27/2020] [Accepted: 07/27/2020] [Indexed: 12/26/2022] Open
Abstract
Arterial calcification is a hallmark of advanced atherosclerosis and predicts cardiovascular events. However, there is no clinically accepted therapy that prevents progression of arterial calcification. HMG-CoA reductase inhibitors, statins, lower low-density lipoprotein-cholesterol and reduce cardiovascular events, but coronary artery calcification is actually promoted by statins. The addition of eicosapentaenoic acid (EPA) to statins further reduced cardiovascular events in clinical trials, JELIS and REDUCE-IT. Additionally, we found that EPA significantly suppressed arterial calcification in vitro and in vivo via suppression of inflammatory responses, oxidative stress and Wnt signaling. However, so far there is a lack of evidence showing the effect of EPA on arterial calcification in a clinical situation. We reviewed the molecular mechanisms of the inhibitory effect of EPA on arterial calcification and the results of some clinical trials.
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Tani M, Tanaka S, Oeda C, Azumi Y, Kawamura H, Sakaue M, Ito M. SLC37A2, a phosphorus-related molecule, increases in smooth muscle cells in the calcified aorta. J Clin Biochem Nutr 2020; 68:23-31. [PMID: 33536709 PMCID: PMC7844665 DOI: 10.3164/jcbn.19-114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 04/04/2020] [Indexed: 11/24/2022] Open
Abstract
Vascular calcification is major source of cardiovascular disease in patients with chronic kidney disease. Hyperphosphatemia leads to increased intracellular phosphorus influx, which leads to an increase in osteoblast-like cells in vascular smooth muscle cell. PiT-1 transports phosphate in vascular smooth muscle cell. However, the mechanism of vascular calcification is not completely understood. This study investigated candidate phosphorus-related molecules other than PiT-1. We hypothesized that phosphorus-related molecules belonging to the solute-carrier (SLC) superfamily would be involved in vascular calcification. As a result of DNA microarray analysis, we focused on SLC37A2 and showed that mRNA expression of these cells increased on calcified aotic smooth muscle cells (AoSMC). SLC37A2 has been reported to transport both glucose-6-phosphate/phosphate and phosphate/phosphate exchanges. In vitro analysis showed that SLC37A2 expression was not affected by inflammation on AoSMC. The expression of SLC37A2 mRNA and protein increased in calcified AoSMC. In vivo analysis showed that SLC37A2 mRNA expression in the aorta of chronic kidney disease rats was correlated with osteogenic marker genes. Furthermore, SLC37A2 was expressed at the vascular calcification area in chronic kidney disease rats. As a result, we showed that SLC37A2 is one of the molecules that increase with vascular calcification in vitro and in vivo.
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Affiliation(s)
- Mariko Tani
- Graduate School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
| | - Sarasa Tanaka
- Graduate School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
| | - Chihiro Oeda
- School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
| | - Yuichi Azumi
- Graduate School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
| | - Hiromi Kawamura
- Graduate School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
| | - Motoyoshi Sakaue
- Graduate School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
| | - Mikiko Ito
- Graduate School of Human Science and Environment, University of Hyogo, 1-1-12 Shinzaike-Honcho, Himeji, Hyogo 670-0092, Japan
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Ghosh S, Luo D, He W, Chen J, Su X, Huang H. Diabetes and calcification: The potential role of anti-diabetic drugs on vascular calcification regression. Pharmacol Res 2020; 158:104861. [PMID: 32407954 DOI: 10.1016/j.phrs.2020.104861] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/22/2020] [Accepted: 04/22/2020] [Indexed: 12/15/2022]
Abstract
Vascular calcification (VC) has been well-established as an independent and strong predictor of cardiovascular diseases (CVD) as well as major cardiac adverse events (MACE). VC is associated with increased mortality in patients with CVD. Pathologically, VC is now believed to be a multi-directional active process ultimately resulting in ectopic calcium deposition in vascular beds. On the other hand, prevalence of diabetes mellitus (DM) is gradually increasing thus making the current population more prone to future CVD. Although the mechanisms involved in development and progression of VC in DM patients are not fully understood, a series of evidences demonstrated positive association between DM and VC. It has been highlighted that different cellular pathways are involved in this process. These intermediates such as tumor necrosis factor alpha (TNF-α), various interleukins (ILs) and different cell-signaling pathways are over-expressed in DM patients leading to development of VC. Thus, considering the burden and significance of VC it is of great importance to find a therapeutic approach to prevent or minimize the development of VC in DM patients. Over the past few years various anti diabetic drugs (ADDs) have been introduced and many of them showed desired glucose control. But no study demonstrated the effects of these medications on regression of VC. In this review, we will briefly discuss the current understanding on DM and VC and how commonly used ADDs modulate the development or progression of VC.
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Affiliation(s)
- Sounak Ghosh
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Dongling Luo
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Wanbing He
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jie Chen
- Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Su
- Tungwah Hospital of Sun Yat-sen University, Dongguan, China
| | - Hui Huang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
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Li Y, Sun Z, Zhang L, Yan J, Shao C, Jing L, Li L, Wang Z. Role of Macrophages in the Progression and Regression of Vascular Calcification. Front Pharmacol 2020; 11:661. [PMID: 32457633 PMCID: PMC7227444 DOI: 10.3389/fphar.2020.00661] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 04/23/2020] [Indexed: 12/15/2022] Open
Abstract
Vascular calcification is an abnormal cell-mediated process in which bone-specific hydroxyapatite crystals are actively deposited on the blood vessel wall and is a significant pathological basis for the increased incidence and mortality of adverse cardiovascular events. Macrophages play an important regulatory role in the occurrence, development, and regression of vascular calcification. After the tissue microenvironment changes, macrophages subsequently change their polarity and phenotype or secrete functional substances as an adaptive response. As research on macrophages continue to move into this field, we gain a new understanding of the mechanism of the formation and regression of vascular calcification, which might offer valuable new intervention targets for the prevention and inhibition of vascular calcification. This review summarizes a wealth of research in this field and explores the roles of macrophages in the development process of vascular calcification.
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Affiliation(s)
- Yalan Li
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jinchuan Yan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lele Jing
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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Tepelenis K, Papathanakos G, Barbouti A, Paraskevas G, Kitsouli A, Alexandra Kefala M, Tepelenis N, Kanavaros P, Kitsoulis P. Phlebosclerosis in lower extremities veins - a systematic review. VASA 2020; 49:349-358. [PMID: 32323629 DOI: 10.1024/0301-1526/a000868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Phlebosclerosis is a venous wall degenerative disease which has gained little popularity in the literature due to its uncertain clinical significance. The objective of this review is to evaluate the epidemiology, etiology and clinical significance of phlebosclerosis in lower extremities veins, particularly the effect of preexisting phlebosclerosis of the great saphenous vein on vein graft patency. Medline was searched from inception until November 1, 2019. Reference lists of included studies were scanned. Only articles published after 1949 were included. Two reviewers independently screened titles/abstracts and full-text papers for any study design in relation to phlebosclerosis in lower extremities veins and abstracted data. A total of 16 Cohort studies and one case-control study (3708 participants, mean age 61.8 years, 59.3 % men, and 40.7 % women) were included after screening 317 titles and abstracts, and 80 full-text articles. The incidence of phlebosclerosis ranged from 1.5-9.7 % depending on the radiological features. On the contrary, the incidence of the phlebosclerotic great saphenous vein prior to its use as a vein graft was 26.9-91 % on histological examination. The small saphenous vein was the most common location of phlebosclerosis followed by the great saphenous vein. There is a link between phlebosclerosis and age, venous insufficiency and haemodialysis. As for the vein graft patency seven studies demonstrated a correlation between preexisting phlebosclerosis and vein graft stenosis, whereas three studies failed to prove any association. In conclusion, the radiological incidence of phlebosclerosis depended on the ultrasound findings. Its presence in the great saphenous vein prior to its use as a vein graft is established on histological examination. The small saphenous vein is mainly affected. Risk factors included age, haemodialysis, and venous insufficiency. Preexisting wall thickness of the great saphenous vein graft seemed to affect negatively its patency in bypass surgery.
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Affiliation(s)
- Kostas Tepelenis
- Department of Surgery, General Hospital of Filiates, Thesprotia, Greece
| | | | - Alexandra Barbouti
- Anatomy - Histology - Embryology, University of Ioannina, Ioannina, Greece
| | | | | | | | | | | | - Panagiotis Kitsoulis
- Anatomy - Histology - Embryology, University of Ioannina, Ioannina, Greece.,Orthopaedics, University of Ioannina, Ioannina, Greece
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Park HJ, Kim Y, Kim MK, Hwang JJ, Kim HJ, Bae SK, Bae MK. Inhibition of Gastrin-Releasing Peptide Attenuates Phosphate-Induced Vascular Calcification. Cells 2020; 9:cells9030737. [PMID: 32192106 PMCID: PMC7140688 DOI: 10.3390/cells9030737] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/09/2020] [Accepted: 03/13/2020] [Indexed: 12/26/2022] Open
Abstract
Vascular calcification is the pathological deposition of calcium/phosphate in the vascular system and is closely associated with cardiovascular morbidity and mortality. Here, we investigated the role of gastrin-releasing peptide (GRP) in phosphate-induced vascular calcification and its potential regulatory mechanism. We found that the silencing of GRP gene and treatment with the GRP receptor antagonist, RC-3095, attenuated the inorganic phosphate-induced calcification of vascular smooth muscle cells (VSMCs). This attenuation was caused by inhibiting phenotype change, apoptosis and matrix vesicle release in VSMCs. Moreover, the treatment with RC-3095 effectively ameliorated phosphate-induced calcium deposition in rat aortas ex vivo and aortas of chronic kidney disease in mice in vivo. Therefore, the regulation of the GRP-GRP receptor axis may be a potential strategy for treatment of diseases associated with excessive vascular calcification.
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Affiliation(s)
- Hyun-Joo Park
- Department of Oral Physiology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50610, Korea; (H.-J.P.); (Y.K.); (M.-K.K.)
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50610, Korea;
| | - Yeon Kim
- Department of Oral Physiology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50610, Korea; (H.-J.P.); (Y.K.); (M.-K.K.)
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50610, Korea;
| | - Mi-Kyoung Kim
- Department of Oral Physiology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50610, Korea; (H.-J.P.); (Y.K.); (M.-K.K.)
| | - Jae Joon Hwang
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Pusan National University, Dental Research Institute, Yangsan 50610, Korea;
| | - Hyung Joon Kim
- Department of Oral Physiology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50610, Korea; (H.-J.P.); (Y.K.); (M.-K.K.)
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50610, Korea;
| | - Soo-Kyung Bae
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50610, Korea;
- Department of Dental Pharmacology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50610, Korea
| | - Moon-Kyoung Bae
- Department of Oral Physiology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50610, Korea; (H.-J.P.); (Y.K.); (M.-K.K.)
- Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan 50610, Korea;
- Correspondence: ; Tel.: +82-51-510-8239
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Klingenschmid G, Tschiderer L, Himmler G, Rungger G, Brugger S, Santer P, Willeit J, Kiechl S, Willeit P. Associations of Serum Dickkopf-1 and Sclerostin With Cardiovascular Events: Results From the Prospective Bruneck Study. J Am Heart Assoc 2020; 9:e014816. [PMID: 32172649 PMCID: PMC7335516 DOI: 10.1161/jaha.119.014816] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Dickkopf-1 and sclerostin have been implicated in atherosclerosis and vascular calcification. We aimed to quantify the association of their serum levels with incident cardiovascular disease (CVD) in the general population. Methods and Results Among 706 participants of the prospective, population-based Bruneck Study, mean±SD of serum levels were 44.5±14.7 pmol/L for dickkopf-1 and 47.1±17.5 pmol/L for sclerostin. The primary outcome was a composite CVD end point composed of ischemic or hemorrhagic stroke, transient ischemic attack, myocardial infarction, angina pectoris, peripheral vascular disease, and revascularization procedures. Over a median follow-up duration of 15.6 years, 179 CVD events occurred. For the primary CVD outcome, multivariable-adjusted hazard ratios (HRs) per SD higher level were 1.20 for dickkopf-1 (95% CI, 1.02-1.42; P=0.028) and 0.92 for sclerostin (95% CI, 0.78-1.08; P=0.286). Secondary outcome analyses revealed that the association of dickkopf-1 was primarily driven by ischemic and hemorrhagic stroke (67 events; HR, 1.37; 95% CI, 1.06-1.78; P=0.017), whereas no increase in risk was observed for transient ischemic attack (22 events; HR, 0.87; 95% CI, 0.53-1.44; P=0.593), myocardial infarction (45 events; HR, 1.10; 95% CI, 0.78-1.54; P=0.598), or for other CVD (45 events; HR, 1.25; 95% CI, 0.88-1.76; P=0.209). Conclusions In this prospective, population-based study, elevated baseline levels of dickkopf-1, but not sclerostin, were independently associated with incident cardiovascular events, which was mainly driven by stroke. Our findings support the hypothesis of a role of dickkopf-1 in the pathogenesis of CVD.
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Affiliation(s)
| | - Lena Tschiderer
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | | | | | - Stefan Brugger
- Departments of Internal Medicine Hospital of Bruneck Italy
| | - Peter Santer
- Departments of Laboratory Medicine Hospital of Bruneck Italy
| | - Johann Willeit
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - Stefan Kiechl
- Department of Neurology Medical University of Innsbruck Innsbruck Austria
| | - Peter Willeit
- Department of Neurology Medical University of Innsbruck Innsbruck Austria.,Department of Public Health and Primary Care University of Cambridge United Kingdom
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Serum IP-10 and IL-17 from Kawasaki disease patients induce calcification-related genes and proteins in human coronary artery smooth muscle cells in vitro. Cell Biosci 2020; 10:36. [PMID: 32190286 PMCID: PMC7066751 DOI: 10.1186/s13578-020-00400-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/04/2020] [Indexed: 01/18/2023] Open
Abstract
Background Kawasaki disease (KD) is one of the major causes of heart disease and vasculitis in children under 5 years old in the world. Clinical evidence has shown that coronary artery calcification may develop in KD patients, however the mechanism has not been elucidated. Previous studies have found that interferon-γ-inducible protein (IP)-10 and interleukin (IL)-17 can be elevated and may play a role in KD development and coronary artery lesion formation. The purpose of this in vitro study was to investigate the possible role of plasma circulating IP-10 and IL-17 of KD patients in vascular calcification development and its underlying mechanism. Result Human coronary artery smooth muscle cells (HCASMCs) were used in this study. We found that HCASMCs treated with IP-10/IL-17-containing KD serum and co-treated with IP-10/IL-17 recombinant proteins could induce a phenotype that may promote vascular calcification by the bone morphogenetic protein (BMP) 6 autocrine effect. Moreover, the BMP6 autocrine stimulation in IP-10/IL-17 co-treated HCASMCs could upregulate the smad1/5-runx2 signaling activation, thus increasing the expression of bone matrix-related proteins, i.e., osteopontin, osteocalcin, and alkaline phosphatase. Conclusions The presented in vitro results provided new insights into the comprehension of the pathogenesis of vascular calcification in SMCs in KD progression. Although additional in vivo experimental models should be completed to confirm the in vivo relevance of these in vitro findings, the results related to the autocrine role of BMP6 may provide a new direction for theranostic drug development to treat KD.
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Rogers MA, Aikawa E. Cardiovascular calcification: artificial intelligence and big data accelerate mechanistic discovery. Nat Rev Cardiol 2020; 16:261-274. [PMID: 30531869 DOI: 10.1038/s41569-018-0123-8] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cardiovascular calcification is a health disorder with increasing prevalence and high morbidity and mortality. The only available therapeutic options for calcific vascular and valvular heart disease are invasive transcatheter procedures or surgeries that do not fully address the wide spectrum of these conditions; therefore, an urgent need exists for medical options. Cardiovascular calcification is an active process, which provides a potential opportunity for effective therapeutic targeting. Numerous biological processes are involved in calcific disease, including matrix remodelling, transcriptional regulation, mitochondrial dysfunction, oxidative stress, calcium and phosphate signalling, endoplasmic reticulum stress, lipid and mineral metabolism, autophagy, inflammation, apoptosis, loss of mineralization inhibition, impaired mineral resorption, cellular senescence and extracellular vesicles that act as precursors of microcalcification. Advances in molecular imaging and big data technology, including in multiomics and network medicine, and the integration of these approaches are helping to provide a more comprehensive map of human disease. In this Review, we discuss ectopic calcification processes in the cardiovascular system, with an emphasis on emerging mechanistic knowledge obtained through patient data and advances in imaging methods, experimental models and multiomics-generated big data. We also highlight the potential and challenges of artificial intelligence, machine learning and deep learning to integrate imaging and mechanistic data for drug discovery.
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Affiliation(s)
- Maximillian A Rogers
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Elena Aikawa
- Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. .,Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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Luna-Luna M, Criales-Vera S, Medina-Leyte D, Díaz-Zamudio M, Flores-Zapata A, Cruz-Robles D, López-Meneses M, Olvera-Cruz S, Ramírez-Marroquín S, Flores-Castillo C, Fragoso JM, Carreón-Torres E, Vargas-Barrón J, Vargas-Alarcón G, Pérez-Méndez Ó. Bone Morphogenetic Protein-2 and Osteopontin Gene Expression in Epicardial Adipose Tissue from Patients with Coronary Artery Disease Is Associated with the Presence of Calcified Atherosclerotic Plaques. Diabetes Metab Syndr Obes 2020; 13:1943-1951. [PMID: 32606854 PMCID: PMC7295210 DOI: 10.2147/dmso.s253632] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 06/04/2020] [Indexed: 12/25/2022] Open
Abstract
PURPOSE It has been proposed that the cardiovascular effects of obesity are related to epicardial adipose tissue (EAT), which seems to play an active role on the development and calcification of atherosclerotic plaques, but the mechanisms are still unknown. Therefore, the aim of this study was to determine whether the EAT expresses the genes of calcifying factors and whether such expression is associated with the body mass index (BMI) and with the presence of coronary artery calcium (CAC) in patients with coronary artery disease (CAD). PATIENTS AND METHODS Forty-three patients with CAD were enrolled specifically for this study, and their CAC score and EAT volume were determined by computed tomography. As the group of comparison, 41 patients with aortic valve stenosis and CAC = 0 were included (control group). A representative subgroup of 16 CAD patients and 23 controls were selected to obtain EAT biopsies during the chirurgical procedure from the atrio-interventricular groove. The mRNA expression of bone morphogenetic protein-2 and -4 (BMP-2, BMP-4), osteopontin (OPN), osteonectin (ON), and osteoprotegerin (OPG) in EAT was determined by qPCR. RESULTS The gene expression of OPN and BMP-2 was 70% and 52% higher in the EAT from CAD patients than that in controls, respectively, whereas the expression of OPG, ON, and BMP-4 was similar in both groups. The EAT volume positively correlated with OPG and with the BMI, suggesting a relationship of obesity with local higher expression of calcifying genes in the coronary territory. The logistic regression analysis showed that high levels of both OPN and BMP-2 increased about 6 and 8 times the odds of coronary calcification (CAC score > 0), respectively. CONCLUSION EAT correlated with BMI and expressed the mRNA of calcifying genes but only OPN and BMP-2 expression was higher in CAD patients. Higher levels of both OPN and BMP-2 statistically determined the presence of calcium in coronary arteries of CAD patients.
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Affiliation(s)
- María Luna-Luna
- Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - Sergio Criales-Vera
- Radiology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - Diana Medina-Leyte
- Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - Mariana Díaz-Zamudio
- Radiology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - Adriana Flores-Zapata
- Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - David Cruz-Robles
- Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - Mauricio López-Meneses
- Adult Cardiology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | - Sergio Olvera-Cruz
- Adult Cardiology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | | | | | - José Manuel Fragoso
- Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | | | - Jesús Vargas-Barrón
- Research Direction, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
| | | | - Óscar Pérez-Méndez
- Molecular Biology, National Institute of Cardiology “Ignacio Chávez”, Mexico City, Mexico
- School of Engineering and Sciences, Tecnológico de Monterrey, Campus Monterrey, Mexico City, Mexico
- Correspondence: Óscar Pérez-Méndez Molecular Biology Department, National Institute of Cardiology “Ignacio Chávez”, Mexico City, MexicoTel +52 55 55732911 ext 26300 Email
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Sun H, Zhang F, Xu Y, Sun S, Wang H, Du Q, Gu C, Black SM, Han Y, Tang H. Salusin-β Promotes Vascular Calcification via Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation. Antioxid Redox Signal 2019; 31:1352-1370. [PMID: 31578871 PMCID: PMC6998059 DOI: 10.1089/ars.2019.7723] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aims: Vascular calcification (VC) is a hallmark feature of cardiovascular disease and a significant risk factor for morbidity and mortality. Salusin-β exerts cardiovascular regulating effects in hypertension, atherosclerosis, and diabetes. The present study was designed to examine the roles of salusin-β in the progression of VC and its downstream signaling mechanisms. Results: Salusin-β expression in both the aortas of VC rats induced by vitamin D3 and nicotine and vascular smooth muscle cells (VSMCs) incubated with calcifying media was increased. Salusin-β knockdown remarkably reduced VC, whereas overexpression of salusin-β exacerbated VC both in vitro and in vivo. Overexpression of salusin-β promoted the VSMC osteochondrogenic transition, decreased Klotho protein levels, enhanced Ras-related C3 botulinum toxin substrate 1 (Rac1) activity and the translocation of p47phox to the membrane, increased the expression of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase subunits and the production of reactive oxygen species (ROS) with or without calcifying media; however, salusin-β deficiency played the opposite roles. The calcification and downregulated Klotho protein levels induced by salusin-β were restored by ROS scavenger N-acetyl-l-cysteine, diphenyleneiodonium chloride [an inhibitor of flavin-containing enzyme, including NAD(P)H oxidase], or gene knockdown of NAD(P)H oxidase (NOX)-2, p22phox, or p47phox but were not affected by NOX-1 and NOX-4 knockdown. Klotho knockdown attenuated the protective effect of salusin-β deficiency on VSMC calcification. By contrast, exogenous Klotho ameliorated the development of VC and ROS generation induced by salusin-β overexpression. Innovation: Salusin-β is a critical modulator in VC. Conclusion: Salusin-β regulates VC through activation of NAD(P)H/ROS-mediated Klotho downregulation, suggesting that salusin-β may be a novel target for treatment of VC.
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Affiliation(s)
- Haijian Sun
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, China.,Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Feng Zhang
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yu Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Shuo Sun
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Huiping Wang
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Qiong Du
- Department of Basic Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Chenxin Gu
- College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Stephen M Black
- Division of Translational and Regenerative Medicine, College of Medicine, Department of Medicine, University of Arizona, Tucson, Arizona
| | - Ying Han
- Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Haiyang Tang
- College of Veterinary Medicine, Northwest A&F University, Yangling, China.,State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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43
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Gourgas O, Cole GB, Muiznieks LD, Sharpe S, Cerruti M. Effect of the Ionic Concentration of Simulated Body Fluid on the Minerals Formed on Cross-Linked Elastin-Like Polypeptide Membranes. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2019; 35:15364-15375. [PMID: 31729882 DOI: 10.1021/acs.langmuir.9b02542] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Deposition of calcium phosphate minerals on the elastin-rich medial layers of arteries can cause severe cardiovascular complications. There are no available treatments for medial calcification, and the mechanism of mineral formation on elastin layers is still unknown. We recently developed an in vitro model of medial calcification using cross-linked elastin-like polypeptide (ELP) membranes immersed in simulated body fluid (SBF). While mineral phase evolution matched that observed in a mouse model of medial calcification, the long incubation required was a practical limitation of this model. Using higher SBF ion concentrations could be a solution to speed up mineral deposition, but its effect on the mineralization process is still not well understood. Here we analyze mineral formation and phase transformation on ELP membranes immersed in high concentration SBF. We show that while mineral deposition is significantly accelerated in these conditions, the chemistry and morphology of the minerals deposited on the ELP membranes and the overall mineralization process are strongly affected. Overall, this work suggests that while the use of low concentration SBF in this in vitro model is more appropriate to study medial calcification associated with the loss of calcification inhibitors, higher SBF ion concentration may be more relevant to study medial calcification in patients with life-threatening diseases such as chronic kidney disease.
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Affiliation(s)
- Ophélie Gourgas
- Department of Mining and Materials Engineering , McGill University , Montreal , Quebec H3A 0C5 , Canada
| | - Gregory B Cole
- Molecular Medicine , Hospital for Sick Children , Toronto , Ontario M5G 0A4 , Canada
- Department of Biochemistry , University of Toronto , Toronto , Ontario M5S 1A8 , Canada
| | - Lisa D Muiznieks
- Molecular Medicine , Hospital for Sick Children , Toronto , Ontario M5G 0A4 , Canada
| | - Simon Sharpe
- Molecular Medicine , Hospital for Sick Children , Toronto , Ontario M5G 0A4 , Canada
- Department of Biochemistry , University of Toronto , Toronto , Ontario M5S 1A8 , Canada
| | - Marta Cerruti
- Department of Mining and Materials Engineering , McGill University , Montreal , Quebec H3A 0C5 , Canada
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Sapkota M, Shrestha SK, Yang M, Park YR, Soh Y. Aloe-emodin inhibits osteogenic differentiation and calcification of mouse vascular smooth muscle cells. Eur J Pharmacol 2019; 865:172772. [PMID: 31697934 DOI: 10.1016/j.ejphar.2019.172772] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/23/2019] [Accepted: 11/01/2019] [Indexed: 02/01/2023]
Abstract
Vascular calcification increases the risk of morbidity and mortality in patients with cardiovascular diseases, chronic kidney diseases, and diabetes. However, viable therapeutic methods to target vascular calcification are limited. Aloe-emodin (AE), an anthraquinone is a natural compound found in the leaves of Aloe-vera. In this study, we investigated the underlying mechanism of AE in the calcification of vascular smooth muscle cells (VSMCs) and murine thoracic aorta. We demonstrate that AE repressed not only the phenotypes of Ca2+ induced calcification but also level of calcium in VSMCs. AE has no effect on cell viability in VSMC cells. Alizarin red, von Kossa stainings and calcium quantification showed that Ca2+ induced vascular calcification is significantly decreased by AE in a concentration-dependent manner. In contrast, AE attenuated Ca2+ induced calcification through inhibiting osteoblast differentiation genes such as SMAD4, collagen 1α, osteopontin (OPN), Runt-related transcription factor (RUNX-2) and Osterix. AE also suppressed Ca2+ induced osteoblast-related protein expression including collagen 1α, bone morphogenic protein 2 (BMP-2), RUNX-2 and smooth muscle actin (SMA). Furthermore, Alizarin red, von Kossa stainings and calcium quantification showed that AE significantly inhibited the calcification of ex vivo ring formation in murine thoracic aorta, and markedly inhibited vitamin D3 induced medial aorta calcification in vivo. Taken together, our findings suggest that AE may have therapeutic potential for the prevention of vascular calcification program.
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Affiliation(s)
- Mahesh Sapkota
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, 561-756, Republic of Korea
| | - Saroj Kumar Shrestha
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, 561-756, Republic of Korea
| | - Ming Yang
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, 561-756, Republic of Korea
| | - Young Ran Park
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, 561-756, Republic of Korea
| | - Yunjo Soh
- Department of Dental Pharmacology, School of Dentistry, Chonbuk National University, Jeon-Ju, 561-756, Republic of Korea.
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45
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Yang CJ, Tsai SH, Wang JC, Chang WC, Lin CY, Tang ZC, Hsu HH. Association between acute aortic dissection and the distribution of aortic calcification. PLoS One 2019; 14:e0219461. [PMID: 31295298 PMCID: PMC6622544 DOI: 10.1371/journal.pone.0219461] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 06/21/2019] [Indexed: 11/19/2022] Open
Abstract
Objective Aortic calcification (AC) is associated with increased risks of cardiovascular events and mortality. Numerous studies have explored the association between calcification and abdominal artery aneurysm. However, evidence regarding the association between AC and acute aortic dissection (AAD) is limited. We aimed to evaluate the association between AC-related variables and the development of intimal tear (IT) in patients with AAD. Methods We conducted a retrospective observational study involving 64 patients with type A AAD and 32 patients with type B AAD from February, 2011 to January, 2017 at a tertiary referral medical center in Taiwan. We used the default analysis module “calcification score analysis” to calculate all the calcification variables, including AC scores and volume. Results We identified an association between AC and AAD. Patients with AAD had a greater AC volume in the aortic arch and greater AC scores for both the ascending aorta and the aortic arch than did patients without AAD. However, hypertension and coronary artery disease, rather than AC remained to be the independent risk factor for AAD in multivariate analysis. Patients with type A AAD had greater mean and cumulative AC volumes in the aortic arch, greater cumulative AC volumes in the whole aorta and higher cumulative AC scores in the aortic arch than did patients with type B AAD. ACs were superimposed on ITs in nearly half of the patients with AAD. In patients with type A AAD, AC was more commonly located distal to the IT and farther from the IT. Conclusions We identified the associations between AC-related variables and the location of IT in patients with AAD. However, AC was not an independent risk factor for AAD. The distribution of AC was different between patients with type A and type B AAD.
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Affiliation(s)
- Chih-Jen Yang
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Shih-Hung Tsai
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan
- * E-mail: (SHT); (HHH)
| | - Jen-Chun Wang
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wei-Chou Chang
- Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Yuan Lin
- Division of Cardiovascular surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Zun-Cheng Tang
- Department of Biological Imaging and Radiological Science, National Yang-Ming University, Taipei, Taiwan
| | - Hsian-He Hsu
- Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- * E-mail: (SHT); (HHH)
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McShane L, Tabas I, Lemke G, Kurowska-Stolarska M, Maffia P. TAM receptors in cardiovascular disease. Cardiovasc Res 2019; 115:1286-1295. [PMID: 30980657 PMCID: PMC6587925 DOI: 10.1093/cvr/cvz100] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 02/28/2019] [Accepted: 04/09/2019] [Indexed: 12/14/2022] Open
Abstract
The TAM receptors are a distinct family of three receptor tyrosine kinases, namely Tyro3, Axl, and MerTK. Since their discovery in the early 1990s, they have been studied for their ability to influence numerous diseases, including cancer, chronic inflammatory and autoimmune disorders, and cardiovascular diseases. The TAM receptors demonstrate an ability to influence multiple aspects of cardiovascular pathology via their diverse effects on cells of both the vasculature and the immune system. In this review, we will explore the various functions of the TAM receptors and how they influence cardiovascular disease through regulation of vascular remodelling, efferocytosis and inflammation. Based on this information, we will suggest areas in which further research is required and identify potential targets for therapeutic intervention.
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Affiliation(s)
- Lucy McShane
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow, UK,Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Ira Tabas
- Departments of Medicine, Physiology, and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Greg Lemke
- Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA,Immunobiology and Microbial Pathogenesis Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
| | - Mariola Kurowska-Stolarska
- Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE), Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow, UK,Corresponding authors. Tel: +44 141 330 7142; E-mail: (P.M.) Tel: +44 141 330 6085; E-mail: (M.K.-S.)
| | - Pasquale Maffia
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow, UK,Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK,Department of Pharmacy, University of Naples Federico II, Naples, Italy,Corresponding authors. Tel: +44 141 330 7142; E-mail: (P.M.) Tel: +44 141 330 6085; E-mail: (M.K.-S.)
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Feng H, Wang JY, Yu B, Cong X, Zhang WG, Li L, Liu LM, Zhou Y, Zhang CL, Gu PL, Wu LL. Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α Inhibits Vascular Calcification Through Sirtuin 3-Mediated Reduction of Mitochondrial Oxidative Stress. Antioxid Redox Signal 2019; 31:75-91. [PMID: 30829051 DOI: 10.1089/ars.2018.7620] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Aims: Vascular calcification is associated with cardiovascular death in patients with chronic kidney disease (CKD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) plays an important role in various cardiovascular diseases. However, its role in vascular calcification remains unknown. Results: Adenine-induced rat CKD model was used to induce arterial medial calcification. The level of PGC-1α decreased in abdominal aorta of CKD rats. Overexpression of PGC-1α significantly ameliorated calcium deposition in rat abdominal aorta, isolated carotid rings, and cultured vascular smooth muscle cells (VSMCs). Mitochondrial reactive oxygen species (mtROS) increased in calcifying aorta and VSMCs. Upregulation of PGC-1α inhibited, whereas PGC-1α depletion promoted β-glycerophosphate-induced mtROS production and calcium deposition. Moreover, PGC-1α increased superoxide dismutase 1 (SOD1) and SOD2 contents in vivo and in vitro, whereas SOD2 deletion eliminated PGC-1α-mediated mtROS change and promoted calcium deposition. Mechanistically, sirtuin 3 (SIRT3) expression declined in calcifying aorta and VSMCs, while PGC-1α overexpression restored SIRT3 expression. Inhibition of SIRT3 by 3-TYP or siRNA (small interfering RNA) reduced PGC-1α-induced upregulation of SOD1 and SOD2, and abolished the protective effect of PGC-1α on calcification of VSMCs. Importantly, PGC-1α was reduced in calcified femoral arteries in CKD patients. In phosphate-induced human umbilical arterial calcification, upregulation of PGC-1α attenuated calcium nodule formation, while this protective effect was abolished by SIRT3 inhibitor. Innovation: We showed for the first time that PGC-1α is an important endogenous regulator against vascular calcification. Induction of PGC-1α could be a potential strategy to treat vascular calcification in CKD patients. Conclusions: PGC-1α protected against vascular calcification by SIRT3-mediated mtROS reduction.
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Affiliation(s)
- Han Feng
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Jin-Yu Wang
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Bo Yu
- 2 Division of Constitutive and Regenerative Sciences, School of Dentistry, University of California, Los Angeles, California
| | - Xin Cong
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Wei-Guang Zhang
- 3 Department of Human Anatomy, Peking University School of Basic Medical Sciences, Beijing, China
| | - Li Li
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Li-Mei Liu
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Yun Zhou
- 4 Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing, China
| | - Cheng-Lin Zhang
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
| | - Pei-Liang Gu
- 3 Department of Human Anatomy, Peking University School of Basic Medical Sciences, Beijing, China
| | - Li-Ling Wu
- 1 Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China
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Kurozumi A, Nakano K, Yamagata K, Okada Y, Nakayamada S, Tanaka Y. IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2. Bone 2019; 124:53-61. [PMID: 30981888 DOI: 10.1016/j.bone.2019.04.006] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/30/2019] [Accepted: 04/11/2019] [Indexed: 12/11/2022]
Abstract
Inflammation and vascular calcification are independent risk factors of cardiovascular events. Vascular smooth muscle cells (VSMCs) exhibit osteoblast-like characteristics in response to various stimuli such as oxidized cholesterol and inflammation. However the precise mechanism of transcriptional regulation of VSMCs by inflammatory stimuli remains unclear. We investigated the process and mechanisms of inflammatory cytokine-induced transformation of human VSMCs (hVSMCs) into osteoblast-like cells, with a special focus on epigenetic changes. Our results demonstrated: (1) interleukin-6 (IL-6)/soluble interleukin-6 receptor (sIL-6R) induced transformation of hVSMCs into an osteoblast phenotype, with subsequent vascular calcification, based on the results of Alizarin Red S staining and O-Cresolphthalein complexone method; (2) IL-6/sIL-6R accelerated the expression of runt-related transcription factor 2 (RUNX2) based on the results of quantitative real-time polymerase chain reaction; (3) Knockdown of signal transducer and activator of transcription (STAT) 3 reduced IL-6/sIL-6R-induced RUNX2 mRNA expression and osteoblast transdifferentiation of hVSMCs; (4) Chromatin immunoprecipitation (ChIP) coupled with PCR (ChIP-PCR) identified a STAT-binding site in RUNX2 promoter region containing trimethylated histone 3 lysine 9 (H3K9me3), a transcriptional repressor, and H3K4me3, a transcriptional enhancer. Stimulation with IL-6/sIL-6R suppressed H3K9me3 but not H3K4me3 through the recruitment of jumonji domain-containing protein (JMJD) 2B, a histone lysine demethylase, at the STAT-binding site in RUNX2 promoter region; (5) IL-6/sIL-6R-induced RUNX2 gene expression was inhibited in hVSMCs pretreated with JIB04, JMJD2 inhibitor, and the inhibitory effect was JIB04 dose-dependent. Our results indicate that the IL-6/STAT3/JMJD2B pathway regulates hVSMCs differentiation into osteoblast-like cells, which suggest its pathogenic role in vascular calcification associated with chronic inflammation.
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Affiliation(s)
- Akira Kurozumi
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Kazuhisa Nakano
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Kaoru Yamagata
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Yosuke Okada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Shingo Nakayamada
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan.
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Abstract
Clinical and preclinical studies over the past 3 decades have uncovered a multitude of signaling pathways involved in the initiation and progression of atherosclerosis. From these studies, signaling by proteins of the Wnt family has recently emerged as an important player in the development of atherosclerosis. Wnt signaling is characterized by a large number of ligands, receptors, and coreceptors and can be regulated at many different levels. Among Wnt modulators, the evolutionary conserved Dkk (Dickkopf) proteins, and especially Dkk-1, the founding member of the family, are the best characterized. The role of Dkks in the pathophysiology of the arterial wall is only partially understood, but their involvement in atherosclerosis is becoming increasingly evident. This review introduces recent key findings on Dkk proteins and their functions in atherosclerosis and discusses the potential importance of modulating Dkk signaling as part of a novel, improved strategy for preventing and treating atherosclerosis-related diseases.
Visual Overview—
An online visual overview is available for this article.
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Affiliation(s)
- Roberta Baetta
- From the Centro Cardiologico Monzino, IRCCS, Milano, Italy
| | - Cristina Banfi
- From the Centro Cardiologico Monzino, IRCCS, Milano, Italy
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50
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Gourgas O, Muiznieks LD, Bello DG, Nanci A, Sharpe S, Cerruti M. Cross-Linked Elastin-like Polypeptide Membranes as a Model for Medial Arterial Calcification. Biomacromolecules 2019; 20:2625-2636. [DOI: 10.1021/acs.biomac.9b00417] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Ophélie Gourgas
- Department of Mining and Materials Engineering, McGill University, Montreal, Quebec H3A 0C5, Canada
| | - Lisa D. Muiznieks
- Molecular Medicine, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Dainelys Guadarrama Bello
- Department of Stomatology, Faculty of Dental Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Antonio Nanci
- Department of Stomatology, Faculty of Dental Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
| | - Simon Sharpe
- Molecular Medicine, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada
| | - Marta Cerruti
- Department of Mining and Materials Engineering, McGill University, Montreal, Quebec H3A 0C5, Canada
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