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1
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Bolha L, Hočevar A, Jurčić V. Current state of epigenetics in giant cell arteritis: Focus on microRNA dysregulation. Autoimmun Rev 2025; 24:103739. [PMID: 39732382 DOI: 10.1016/j.autrev.2024.103739] [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: 09/18/2024] [Revised: 12/23/2024] [Accepted: 12/25/2024] [Indexed: 12/30/2024]
Abstract
Giant cell arteritis (GCA) is a primary systemic vasculitis affecting the elderly, characterized by a granulomatous vessel wall inflammation of large- and medium-sized arteries. The immunopathology of GCA is complex, involving both the innate and adaptive arms of the immune system, where a maladaptive inflammatory-driven vascular repair process ultimately results in vessel wall thickening, intramural vascular smooth muscle cell proliferation, neovascularization and vessel lumen occlusion, which can lead to serious ischemic complications such as visual loss and ischemic stroke. Over the past decade, microRNA (miRNA) dysregulation has been highlighted as an important contributing factor underlying the pathogenesis of GCA. Since current understanding of miRNA involvement in GCA remains largely based on extrapolation of previously determined miRNA functions in vitro or in loss- or gain-of-function studies, an overall insight into the role of miRNA alteration in GCA pathophysiology remains limited. In this narrative review, we summarize the current knowledge on aberrantly expressed miRNAs in GCA and thoroughly discuss the impact of their altered regulatory role in the context of GCA setting. Furthermore, we address challenges and future perspectives in utilization of miRNA-based diagnostic and prognostic biomarkers of GCA in clinical settings.
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Affiliation(s)
- Luka Bolha
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
| | - Alojzija Hočevar
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Vesna Jurčić
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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2
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He L, Liu Y, Widlansky ME, Kriegel AJ, Qiu Q, Liang M. microRNA and Hypertension. Hypertension 2025; 82:181-184. [PMID: 39633557 PMCID: PMC11893092 DOI: 10.1161/hypertensionaha.124.21728] [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] [Indexed: 12/07/2024]
Abstract
Several microRNAs (miRNAs) strongly influence blood pressure and the development of hypertension by modulating vascular, renal, and other physiological mechanisms. In addition, miRNAs may contribute to the genetic regulation of blood pressure. Future research should focus on investigating select miRNAs with potent physiological effects, understanding cellular context-dependent mechanisms conferring specificity to miRNA action, and integrating miRNAs as powerful modulators into the molecular system that underlies the regulation of blood pressure and the development of hypertension.
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Affiliation(s)
- Lishu He
- Department of Physiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yong Liu
- Department of Physiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona
| | - Michael E. Widlansky
- Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Alison J. Kriegel
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Qiongzi Qiu
- Department of Physiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona
| | - Mingyu Liang
- Department of Physiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona
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3
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Minatoguchi S, Sugito N, Heishima K, Ito Y, Nakashima R, Okura H, Akao Y, Minatoguchi S. Restoration effect of chemically modified microRNA-143-3p on acute myocardial infarction in animal models. Sci Rep 2025; 15:1107. [PMID: 39774185 PMCID: PMC11707079 DOI: 10.1038/s41598-024-76429-3] [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] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 10/14/2024] [Indexed: 01/11/2025] Open
Abstract
We investigated whether miR143#12, a synthesized chemically modified miR-143-3p derivative, exerts therapeutic effects on acute myocardial infarction (AMI). Sprague-Dawley rats and Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 weeks of reperfusion. The rat AMI model was intravenously administered with control miRNA (9 μg/kg), 3 μg/kg or 9 μg/kg of miR143#12 1 h after reperfusion, while the rabbit AMI model was intravenously administered with control miRNA (9 μg/kg) or 9 μg/kg of miR143#12. In the rat and rabbit AMI models, 9 μg/kg of miR143#12 significantly reduced infarct sizes and significantly improved cardiac function including LVEF and LVFS at 2 weeks. The tissue miR143 levels in infarct areas significantly decreased after AMI in both models. Electron microscopic study and immunohistochemistry suggested that miR143#12 suppressed autophagic cell death caused by AMI and induced neoangiogenesis in the infarct border. In cultured rat H9c2 cells, miR143#12 significantly inhibited H2O2-induced autophagic cell death by decreasing ROS levels and increased viable cell numbers more than the control by silencing COX-1, -2, and ATG7. Replacement treatment with miR143#12 in the infarct areas, where the expression levels of miR143 were significantly decreased, has a beneficial effect on AMI by silencing COX-1 and -2.
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Affiliation(s)
- Shingo Minatoguchi
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Nobuhiko Sugito
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Kazuki Heishima
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Yuko Ito
- Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Remi Nakashima
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
| | - Hiroyuki Okura
- Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yukihiro Akao
- United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
| | - Shinya Minatoguchi
- Department of Circulatory and Respiratory Advanced Medicine, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu, 501-1194, Japan.
- Cardiology, Gifu Municipal Hospital, Gifu, Japan.
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4
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Brown SD, Klimi E, Bakker WAM, Beqqali A, Baker AH. Non-coding RNAs to treat vascular smooth muscle cell dysfunction. Br J Pharmacol 2025; 182:246-280. [PMID: 38773733 DOI: 10.1111/bph.16409] [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: 11/17/2023] [Revised: 02/19/2024] [Accepted: 03/14/2024] [Indexed: 05/24/2024] Open
Abstract
Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis and vein graft failure. Recent advances have unveiled a fascinating range of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. We also discuss the prospects and challenges associated with developing ncRNA-based therapies for this prevalent type of cardiovascular pathology. LINKED ARTICLES: This article is part of a themed issue Non-coding RNA Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.2/issuetoc.
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MESH Headings
- Animals
- Humans
- Cardiovascular Diseases/drug therapy
- Cardiovascular Diseases/genetics
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/pathology
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- RNA, Circular/genetics
- RNA, Circular/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- RNA, Untranslated/pharmacology
- RNA, Untranslated/therapeutic use
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Affiliation(s)
- Simon D Brown
- BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Eftychia Klimi
- BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | | | - Abdelaziz Beqqali
- BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Andrew H Baker
- BHF Centre for Cardiovascular Science, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands
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5
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Lu Z, Zhu S, Wu Y, Xu X, Li S, Huang Q. Circ_0008571 modulates the phenotype of vascular smooth muscle cells by targeting miR-145-5p in intracranial aneurysms. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167278. [PMID: 38834101 DOI: 10.1016/j.bbadis.2024.167278] [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: 10/30/2023] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND The dysfunction of human vascular smooth cells (hVSMCs) is significantly connected to the development of intracranial aneurysms (IAs). By suppressing the activity of microRNAs (miRNAs), circular RNAs (circRNAs) participate in IA pathogenesis. Nevertheless, the role of hsa_circ_0008571 in IAs remains unclear. METHODS circRNA sequencing was used to identify circRNAs from human IA tissues. To determine the function of circ_0008571, Transwell, wound healing, and cell proliferation assays were conducted. To identify the target of circ_0008571, the analyses of CircInteractome and TargetScan, as well as the luciferase assay were carried out. Furthermore, circ_0008571 knockdown and over-expression were performed to investigate its functions in IA development and the underlying molecular mechanisms. RESULTS Both hsa_circ_0008571 and Integrin beta 8 (ITGB8) were downregulated, while miR-145-5p transcription was elevated in the aneurysm wall of IAs patients compared to superficial temporal artery tissues. In vitro, cell migration and growth were dramatically suppressed after hsa_circ_0008571 overexpression. Mechanistically, has_circ_0008571 could suppress miR-145-5p activity by direct sponging. Moreover, we found that ITGB8 expression and the activation of the TGF-β-mediated signaling pathway were significantly enhanced. CONCLUSION The hsa_circ_0008571-miR-145-5p-ITGB8 axis plays an essential role in IA progression.
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Affiliation(s)
- Zhiwen Lu
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai 200433, China; Department of Neurosurgery, Naval Medical Center, The PLA Naval Medical University, Shanghai 200052, China
| | - Shijie Zhu
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yina Wu
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Xiaolong Xu
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Siqi Li
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Qinghai Huang
- Department of Neurovascular Centre, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
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6
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Luo J, Wang L, Cui C, Chen H, Zeng W, Li X. MicroRNA-19a-3p inhibits endothelial dysfunction in atherosclerosis by targeting JCAD. BMC Cardiovasc Disord 2024; 24:394. [PMID: 39080547 PMCID: PMC11287888 DOI: 10.1186/s12872-024-04063-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/19/2024] [Indexed: 08/03/2024] Open
Abstract
OBJECTIVE To examine the influences and mechanisms of MicroRNA-19a-3p (miR-19a-3p) on endothelial dysfunction in atherosclerosis. METHODS An analysis of miR-19a expression was carried out using the Gene Expression Omnibus (GEO) database. The effect of miR-19a-3p on endothelial function in HUVECs was evaluated by miR-19a-3p overexpression under TNF-α treatment. Luciferase assays were performed to explore the potential target genes. Overexpression of junctional protein associated with coronary artery disease (JCAD) was used to examine the effects of miR-19a-3p on cell adhesion, and proliferation. RESULTS MiR-19a-3p expression in endothelial cells decreased after exposure to TNF-α and/or oscillatory flow, consistent with the expression change of miR-19a-3p found in atherosclerotic plaques. Additionally, endothelial cell dysfunction and inflammation were significantly diminished by miR-19a-3p overexpression but markedly exacerbated by miR-19a-3p inhibition. MiR-19a-3p transfection significantly decreased the expression of JCAD by binding to the 3'-UTR of JCAD mRNA. Furthermore, the protective effect of miR-19a-3p against endothelial cell dysfunction and inflammation was achieved by regulating JCAD and was closely linked to the Hippo/YAP signaling pathway. CONCLUSION MiR-19a-3p expression is a crucial molecular switch in the onset of atherosclerosis and miR-19a-3p overexpression is a possible pharmacological therapeutic strategy for reversing the development of atherosclerosis.
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Affiliation(s)
- Jinque Luo
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
- College of Pharmacy, Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha, 410219, Hunan, China
| | - Ling Wang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
- College of Pharmacy, Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical University, Changsha, 410219, Hunan, China
| | - Chaoyue Cui
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
| | - Hongyu Chen
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
| | - Wanli Zeng
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China
| | - Xin Li
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, "The 14th Five-Year Plan" Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, 1501 Leifeng Avenue, Changsha, 410219, Hunan, China.
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7
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Kornfeld SF, Cummings SE, Yaworski R, De Repentigny Y, Gagnon S, Zandee S, Fathi S, Prat A, Kothary R. Loss of miR-145 promotes remyelination and functional recovery in a model of chronic central demyelination. Commun Biol 2024; 7:813. [PMID: 38965401 PMCID: PMC11224363 DOI: 10.1038/s42003-024-06513-x] [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: 09/23/2020] [Accepted: 06/27/2024] [Indexed: 07/06/2024] Open
Abstract
Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.
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Affiliation(s)
- Samantha F Kornfeld
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Sarah E Cummings
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Rebecca Yaworski
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada
| | - Yves De Repentigny
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
| | - Sabrina Gagnon
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
| | - Stephanie Zandee
- Neuroimmunology Unit and Multiple Sclerosis Clinic, The Research Center of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Samaneh Fathi
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada
| | - Alexandre Prat
- Neuroimmunology Unit and Multiple Sclerosis Clinic, The Research Center of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Rashmi Kothary
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
- Department of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
- Centre for Neuromuscular Disease, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
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8
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Liu N, Jiang X, Zhang G, Long S, Li J, Jiang M, Jia G, Sun R, Zhang L, Zhang Y. LncRNA CARMN m6A demethylation by ALKBH5 inhibits mutant p53-driven tumour progression through miR-5683/FGF2. Clin Transl Med 2024; 14:e1777. [PMID: 39039912 PMCID: PMC11263751 DOI: 10.1002/ctm2.1777] [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: 02/05/2024] [Revised: 06/25/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024] Open
Abstract
N-methyladenosine (m6A) represents a prevalent RNA modification observed in colorectal cancer. Despite its abundance, the biological implications of m6A methylation on the lncRNA CARMN remain elusive in colorectal cancer, especially for mutant p53 gain-of-function. Here, we elucidate that CARMN exhibits diminished expression levels in colorectal cancer patients with mutant p53, attributed to its rich m6A methylation, which promotes cancer proliferation, invasion and metastasis in vitro and in vivo. Further investigation illustrates that ALKBH5 acts as a direct demethylase of CARMN, targeting 477 methylation sites, thereby preserving CARMN expression. However, the interaction of mutant p53 with the ALKBH5 promoter impedes its transcription, enhancing m6A methylation levels on CARMN. Subsequently, YTHDF2/YTHDF3 recognise and degrade m6A-modified CARMN. Concurrently, overexpressing CARMN significantly suppressed colorectal cancer progression in vitro and in vivo. Additionally, miR-5683 was identified as a direct downstream target of lncRNA CARMN, exerting an antitumour effect by cooperatively downregulating FGF2 expression. Our findings revealed the regulator and functional mechanism of CARMN in colorectal cancer with mutant p53, potentially offering insights into demethylation-based strategies for cancer diagnosis and therapy. The m6A methylation of CARMN that is prime for mutant p53 gain-of-function-induced malignant progression of colorectal cancer, identifying a promising approach for cancer therapy.
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Affiliation(s)
- Nannan Liu
- School of Biomedical SciencesHunan UniversityChangshaChina
| | - Xinxiu Jiang
- School of Biomedical SciencesHunan UniversityChangshaChina
| | - Ge Zhang
- Department of Laboratory MedicineThe Third Xiangya HospitalCentral South UniversityChangshaChina
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Shuaiyu Long
- Hebei Provincial Mental Health CenterHebei Key Laboratory of Major Mental and Behavioral DisordersThe Sixth Clinical Medical College of Hebei UniversityBaodingHebeiChina
| | - Jiehan Li
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Meimei Jiang
- School of Biomedical SciencesHunan UniversityChangshaChina
| | - Guiyun Jia
- School of Biomedical SciencesHunan UniversityChangshaChina
| | - Renyuan Sun
- Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lingling Zhang
- Department of Laboratory MedicineThe Third Xiangya HospitalCentral South UniversityChangshaChina
| | - Yingjie Zhang
- School of Biomedical SciencesHunan UniversityChangshaChina
- Department of GastroenterologyHuadong Hospital, Shanghai Medical College, Fudan UniversityShanghaiP.R. China
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9
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La Chica Lhoëst MT, Martinez A, Claudi L, Garcia E, Benitez-Amaro A, Polishchuk A, Piñero J, Vilades D, Guerra JM, Sanz F, Rotllan N, Escolà-Gil JC, Llorente-Cortés V. Mechanisms modulating foam cell formation in the arterial intima: exploring new therapeutic opportunities in atherosclerosis. Front Cardiovasc Med 2024; 11:1381520. [PMID: 38952543 PMCID: PMC11215187 DOI: 10.3389/fcvm.2024.1381520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/28/2024] [Indexed: 07/03/2024] Open
Abstract
In recent years, the role of macrophages as the primary cell type contributing to foam cell formation and atheroma plaque development has been widely acknowledged. However, it has been long recognized that diffuse intimal thickening (DIM), which precedes the formation of early fatty streaks in humans, primarily consists of lipid-loaded smooth muscle cells (SMCs) and their secreted proteoglycans. Recent studies have further supported the notion that SMCs constitute the majority of foam cells in advanced atherosclerotic plaques. Given that SMCs are a major component of the vascular wall, they serve as a significant source of microvesicles and exosomes, which have the potential to regulate the physiology of other vascular cells. Notably, more than half of the foam cells present in atherosclerotic lesions are of SMC origin. In this review, we describe several mechanisms underlying the formation of intimal foam-like cells in atherosclerotic plaques. Based on these mechanisms, we discuss novel therapeutic approaches that have been developed to regulate the generation of intimal foam-like cells. These innovative strategies hold promise for improving the management of atherosclerosis in the near future.
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Affiliation(s)
- M. T. La Chica Lhoëst
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | - A. Martinez
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | - L. Claudi
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | - E. Garcia
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | - A. Benitez-Amaro
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | - A. Polishchuk
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
| | - J. Piñero
- Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences (DCEXS), Hospital del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - D. Vilades
- Department of Cardiology, Hospital de la Santa Creu I Sant Pau, Biomedical Research Institute Sant Pau (IIB-SANTPAU), Universitat Autonoma de Barcelona, Barcelona, Spain
- Department of Cardiovascular, CIBERCV, Institute of Health Carlos III, Madrid, Spain
| | - J. M. Guerra
- Department of Cardiology, Hospital de la Santa Creu I Sant Pau, Biomedical Research Institute Sant Pau (IIB-SANTPAU), Universitat Autonoma de Barcelona, Barcelona, Spain
- Department of Cardiovascular, CIBERCV, Institute of Health Carlos III, Madrid, Spain
| | - F. Sanz
- Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences (DCEXS), Hospital del Mar Medical Research Institute (IMIM), Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - N. Rotllan
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
- Department of Cardiovascular, CIBERDEM, Institute of Health Carlos III, Madrid, Spain
| | - J. C. Escolà-Gil
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
- Department of Cardiovascular, CIBERDEM, Institute of Health Carlos III, Madrid, Spain
| | - V. Llorente-Cortés
- Department of Experimental Pathology, Institute of Biomedical Research of Barcelona (IIBB)-Spanish National Research Council (CSIC), Barcelona, Spain
- Department of Cardiovascular, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain
- Department of Cardiovascular, CIBERCV, Institute of Health Carlos III, Madrid, Spain
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10
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Kang K, Sun C, Li H, Liu X, Deng J, Chen S, Zeng L, Chen J, Liu X, Kuang J, Xiang J, Cheng J, Liao X, Lin M, Zhang X, Zhan C, Liu S, Wang J, Niu Y, Liu C, Liang C, Zhu J, Liang S, Tang H, Gou D. N6-methyladenosine-driven miR-143/145-KLF4 circuit orchestrates the phenotypic switch of pulmonary artery smooth muscle cells. Cell Mol Life Sci 2024; 81:256. [PMID: 38866991 PMCID: PMC11335293 DOI: 10.1007/s00018-024-05304-1] [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: 10/09/2023] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/14/2024]
Abstract
Pulmonary hypertension (PH) is characterized by vascular remodeling predominantly driven by a phenotypic switching in pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms for this phenotypic alteration remain incompletely understood. Here, we identified that RNA methyltransferase METTL3 is significantly elevated in the lungs of hypoxic PH (HPH) mice and rats, as well as in the pulmonary arteries (PAs) of HPH rats. Targeted deletion of Mettl3 in smooth muscle cells exacerbated hemodynamic consequences of hypoxia-induced PH and accelerated pulmonary vascular remodeling in vivo. Additionally, the absence of METTL3 markedly induced phenotypic switching in PASMCs in vitro. Mechanistically, METTL3 depletion attenuated m6A modification and hindered the processing of pri-miR-143/145, leading to a downregulation of miR-143-3p and miR-145-5p. Inhibition of hnRNPA2B1, an m6A mediator involved in miRNA maturation, similarly resulted in a significant reduction of miR-143-3p and miR-145-5p. We demonstrated that miR-145-5p targets Krüppel-like factor 4 (KLF4) and miR-143-3p targets fascin actin-bundling protein 1 (FSCN1) in PASMCs. The decrease of miR-145-5p subsequently induced an upregulation of KLF4, which in turn suppressed miR-143/145 transcription, establishing a positive feedback circuit between KLF4 and miR-143/145. This regulatory circuit facilitates the persistent suppression of contractile marker genes, thereby sustaining PASMC phenotypic switch. Collectively, hypoxia-induced upregulation of METTL3, along with m6A mediated regulation of miR-143/145, might serve as a protective mechanism against phenotypic switch of PASMCs. Our results highlight a potential therapeutic strategy targeting m6A modified miR-143/145-KLF4 loop in the treatment of PH.
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Affiliation(s)
- Kang Kang
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Chuannan Sun
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Hui Li
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Xiaojia Liu
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Jingyuan Deng
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Silei Chen
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Le Zeng
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Jiahao Chen
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Xinyi Liu
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Jiahao Kuang
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Jingjing Xiang
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Jingqian Cheng
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Xiaoyun Liao
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Mujin Lin
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Xingshi Zhang
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Chuzhi Zhan
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Sisi Liu
- Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen, 518060, Guangdong, China
| | - Jun Wang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Yanqin Niu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Cuilian Liu
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Cai Liang
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Jinsheng Zhu
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
| | - Shuxin Liang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
| | - Haiyang Tang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China
| | - Deming Gou
- Shenzhen Key Laboratory of Microbial Genetic Engineering, Vascular Disease Research Center, College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory of Regional Immunity and Disease, Carson International Cancer Center, School of Medicine, Shenzhen University, Shenzhen, 518060, China.
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11
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Rasmi Y, Mohamed YA, Alipour S, Ahmed S, Abdelmajed SS. The role of miR-143/miR-145 in the development, diagnosis, and treatment of diabetes. J Diabetes Metab Disord 2024; 23:39-47. [PMID: 38932869 PMCID: PMC11196424 DOI: 10.1007/s40200-023-01317-y] [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: 08/20/2023] [Accepted: 09/14/2023] [Indexed: 06/28/2024]
Abstract
Objectives Diabetes mellitus [DM], is a multifaceted metabolic disease, which has become a worldwide threat to human wellness. Over the past decades, an enormous amount of attention has been devoted to understanding how microRNAs [miRNAs], a class of small non-coding RNA regulators of gene expression at the post-transcriptional level, are tied to DM pathology. It has been demonstrated that miRNAs control insulin synthesis, secretion, and activity. This review aims to provide an evaluation of the use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes. Methods The use of miR-143 and miR-145 as biomarkers for the diagnosis and prognosis of diabetes has been studied, and research that examined this link was sought after in the literature. In addition, we will discuss the cellular and molecular pathways of insulin secretion regulation by miR-143/145 expression and finally their role in diabetes. Results In the current review, we emphasize recent findings on the miR-143/145 expression profiles as novel DM biomarkers in clinical studies and animal models and highlight recent discoveries on the complex regulatory effect and functional role of miR-143/145 expression in DM. Conclusion A novel clinical treatment that alters the expression and activity of miR-143/miR-145 may be able to return cells to their natural state of glucose homeostasis, demonstrating the value of using comprehensive miRNA profiles to predict the beginning of diabetes. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-023-01317-y.
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Affiliation(s)
- Yousef Rasmi
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Cellular and Molecular Research Center, Cellular and Molecular Research Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Yara Ahmed Mohamed
- Faculty of Biotechnology, October University for Modern Sciences and Arts University [MSA], Giza, Egypt
| | - Shahriar Alipour
- Cellular and Molecular Research Center, Cellular and Molecular Research Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Salma Ahmed
- Faculty of Biotechnology, October University for Modern Sciences and Arts University [MSA], Giza, Egypt
| | - Samar Samir Abdelmajed
- Faculty of Dentistry- Medical Biochemistry and Genetics department, October University for Modern Sciences and Arts University [MSA], Giza, Egypt
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12
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Boen HM, Cherubin M, Franssen C, Gevaert AB, Witvrouwen I, Bosman M, Guns PJ, Heidbuchel H, Loeys B, Alaerts M, Van Craenenbroeck EM. Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2024; 6:183-199. [PMID: 38774014 PMCID: PMC11103047 DOI: 10.1016/j.jaccao.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 12/11/2023] [Accepted: 12/19/2023] [Indexed: 05/24/2024] Open
Abstract
Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage. Exploring new, more specific biomarkers with a clear link to the underlying pathomechanism of cardiotoxicity holds promise for increased specificity and sensitivity in detecting early anthracycline-induced cardiotoxicity. miRNAs (microRNAs), small single-stranded, noncoding RNA sequences involved in epigenetic regulation, influence various physiological and pathological processes by targeting expression and translation. Emerging as new biomarker candidates, circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link. This review comprehensively outlines their potential as early biomarkers for cardiotoxicity and their pathomechanistic link.
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Affiliation(s)
- Hanne M. Boen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Martina Cherubin
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Constantijn Franssen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Andreas B. Gevaert
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Isabel Witvrouwen
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Matthias Bosman
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Pieter-Jan Guns
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Hein Heidbuchel
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
| | - Bart Loeys
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Maaike Alaerts
- Centrum of Medical Genetics, GENCOR, University of Antwerp, Antwerp, Belgium
| | - Emeline M. Van Craenenbroeck
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Antwerp, Belgium
- Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium
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13
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Wei S, Pei J, Belser P, Lee T, Farma JM, Patchefsky AS, Flieder DB, Montgomery EA. Novel MIR143HG::PLAG1 gene fusion identified in a rectal myxoid leiomyosarcoma. Genes Chromosomes Cancer 2024; 63:e23239. [PMID: 38656544 DOI: 10.1002/gcc.23239] [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: 02/09/2024] [Revised: 03/21/2024] [Accepted: 04/06/2024] [Indexed: 04/26/2024] Open
Abstract
Myxoid leiomyosarcoma (MLS) is a rare but well-documented tumor that often portends a poor prognosis compared to the conventional leiomyosarcoma. This rare sarcoma has been reported in the uterus, external female genitalia, soft tissue, and other locations. However, a definite rectal MLS has not been reported. Recently five cases of MLS were reported to harbor PLAG1 fusions (TRPS1::PLAG1, RAD51B::PLAG1, and TRIM13::PLAG1). In this report, we present a case of rectal MLS with a novel MIR143HG::PLAG1 fusion detected by RNA next-generation sequencing.
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Affiliation(s)
- Shuanzeng Wei
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Jianming Pei
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Paul Belser
- Department of Pathology and Laboratory Medicine, Jefferson Einstein Montgomery Hospital, East Norriton, Pennsylvania, USA
| | - Teresa Lee
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Jeffrey M Farma
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Arthur S Patchefsky
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Douglas B Flieder
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Elizabeth A Montgomery
- Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA
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14
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Searles CD. MicroRNAs and Cardiovascular Disease Risk. Curr Cardiol Rep 2024; 26:51-60. [PMID: 38206553 PMCID: PMC10844442 DOI: 10.1007/s11886-023-02014-1] [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] [Accepted: 12/10/2023] [Indexed: 01/12/2024]
Abstract
PURPOSE OF REVIEW MicroRNAs (miRNAs)-short, non-coding RNAs-play important roles in almost all aspects of cardiovascular biology, and changes in intracellular miRNA expression are indicative of cardiovascular disease development and progression. Extracellular miRNAs, which are easily measured in blood and can be reflective of changes in intracellular miRNA levels, have emerged as potential non-invasive biomarkers for disease. This review summarizes current knowledge regarding miRNAs as biomarkers for assessing cardiovascular disease risk and prognosis. RECENT FINDINGS Numerous studies over the last 10-15 years have identified associations between extracellular miRNA profiles and cardiovascular disease, supporting the potential use of extracellular miRNAs as biomarkers for risk stratification. However, clinical application of extracellular miRNA profiles has been hampered by poor reproducibility and inter-study variability that is due largely to methodological differences between studies. While recent studies indicate that circulating extracellular miRNAs are promising biomarkers for cardiovascular disease, evidence for clinical implementation is lacking. This highlights the need for larger, well-designed studies that use standardized methods for sample preparation, miRNA isolation, quantification, and normalization.
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Affiliation(s)
- Charles D Searles
- Emory University School of Medicine and Atlanta VA Health Care System, 1670 Clairmont Road, Decatur, GA, 30033, USA.
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15
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ZENUNAJ G. The role of circulating miRNAs as predictive biomarkers for the neointimal hyperplasia after femoro-popliteal endovascular procedures for symptomatic peripheral arterial disease. ITALIAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY 2024; 30. [DOI: 10.23736/s1824-4777.23.01634-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
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16
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Parsamanesh N, Poudineh M, Siami H, Butler AE, Almahmeed W, Sahebkar A. RNA interference-based therapies for atherosclerosis: Recent advances and future prospects. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 204:1-43. [PMID: 38458734 DOI: 10.1016/bs.pmbts.2023.12.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2024]
Abstract
Atherosclerosis represents a pathological state that affects the arterial system of the organism. This chronic, progressive condition is typified by the accumulation of atheroma within arterial walls. Modulation of RNA molecules through RNA-based therapies has expanded the range of therapeutic options available for neurodegenerative diseases, infectious diseases, cancer, and, more recently, cardiovascular disease (CVD). Presently, microRNAs and small interfering RNAs (siRNAs) are the most widely employed therapeutic strategies for targeting RNA molecules, and for regulating gene expression and protein production. Nevertheless, for these agents to be developed into effective medications, various obstacles must be overcome, including inadequate binding affinity, instability, challenges of delivering to the tissues, immunogenicity, and off-target toxicity. In this comprehensive review, we discuss in detail the current state of RNA interference (RNAi)-based therapies.
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Affiliation(s)
- Negin Parsamanesh
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Haleh Siami
- School of Medicine, Islamic Azad University of Medical Science, Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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17
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Wagh V, Nguemo F, Kiseleva Z, Mader RM, Hescheler J, Mohl W. Circulating microRNAs and cardiomyocyte proliferation in heart failure patients related to 10 years survival. ESC Heart Fail 2023; 10:3559-3572. [PMID: 37752740 PMCID: PMC10682869 DOI: 10.1002/ehf2.14516] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 07/17/2023] [Accepted: 08/18/2023] [Indexed: 09/28/2023] Open
Abstract
AIMS Mechanochemical signalling drives organogenesis and is highly conserved in mammal evolution. Regaining recovery in myocardial jeopardy by inducing principles linking cardiovascular therapy and clinical outcome has been the dream of scientists for decades. Concepts involving embryonic pathways to regenerate adult failing hearts became popular in the early millennium. Since then, abundant data on stem cell research have been published, never reaching widespread application in heart failure therapy. Another conceptual access, using mechanotransduction in cardiac veins to limit myocardial decay, is pressure-controlled intermittent coronary sinus occlusion (PICSO). Recently, we reported acute molecular signs and signals of PICSO activating regulatory miRNA and inducing cell proliferation mimicking cardiac development in adult failing hearts. According to a previously formulated hypothesis, 'embryonic recall', this study aimed to define molecular signals involved in endogenous heart repair during PICSO and study their relation to patient survival. METHODS AND RESULTS We previously reported a study on the acute molecular effects of PICSO in an observational non-randomized study. Eight out of the thirty-two patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) were treated with PICSO. Survival was monitored over 10 years, and coronary sinus blood samples were collected during intervention before and after 20 min and tested for miRNA signalling and proliferation when co-cultured with cardiomyocytes. A numerically lower death rate post-CRT and PICSO as compared with control CRT only, and a non-significant reduction in all-cause mortality risk of 42% was observed (37.5% vs. 54.0%, relative risk = 0.58, 95% confidence interval: 0.17-2.05; P = 0.402). Four miRNAs involved in cell cycle, proliferation, morphogenesis, embryonic development, and apoptosis significantly increased concomitantly in survivors and PICSO compared with a decrease in non-survivors (hsa-miR Let7b, P < 0.01; hsa-miR- 421, P < 0.006; hsa-miR 363-3p, P < 0.03 and hsa-miR 19b-3p P < 0.01). In contrast, three miRNAs involved in proliferation and survival, determining cell fate, and recycling endosomes decreased in survivors and PICSO (hsa miR 101-3p, P < 0.03; hsa-miR 25-3p, P < 002; hsa-miR 30d-5p P < 0.04). In vitro cellular proliferation increased in survivors and lowered in non-survivors showing a pattern distinction, discriminating longevity according to up to 10-year survival in heart failure patients. CONCLUSIONS This study proposes that generating regenerative signals observed during PICSO intervention relate to patient outcomes. Morphogenetic pathways induced by periods of flow reversal in cardiac veins in a domino-like pattern transform embryonic into regenerative signals. Studies supporting the conversion of mechanochemical signals into regenerative molecules during PICSO are warranted to substantiate predictive power on patient longevity, opening new therapeutic avenues in otherwise untreatable heart failure.
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Affiliation(s)
- Vilas Wagh
- Merck Research LabsBostonMAUSA
- Center of Physiology and Pathophysiology, Institute of NeurophysiologyUniversity of CologneCologneGermany
| | - Filomain Nguemo
- Center of Physiology and Pathophysiology, Institute of NeurophysiologyUniversity of CologneCologneGermany
| | - Zlata Kiseleva
- Department of Cardiac Surgery emeritusMedical University ViennaViennaAustria
| | - Robert M. Mader
- Department of Medicine IMedical University ViennaViennaAustria
| | - Juergen Hescheler
- Center of Physiology and Pathophysiology, Institute of NeurophysiologyUniversity of CologneCologneGermany
| | - Werner Mohl
- Department of Cardiac Surgery emeritusMedical University ViennaViennaAustria
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18
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Qu Y, Huang X, Zhang W, He X, Chen Z, Zhang Y, Gu N. Differentially expressed miR-127, miR-150, and miR-145 in serum extracellular vesicles are novel diagnostic biomarkers of unstable angina. Cardiovasc Diagn Ther 2023; 13:866-878. [PMID: 37941844 PMCID: PMC10628431 DOI: 10.21037/cdt-22-575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 07/14/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND Specific and sensitive diagnostic biomarkers for unstable angina (UA) are currently scarce. The diagnosis of UA usually relies on medical history and physician experience. This study aimed to analyze the expression profiles of microRNAs (miRNAs) in the serum extracellular vesicles (EVs) of UA patients, thus identifying potential diagnostic biomarkers of UA. METHODS This study is a prospective study and participants were recruited randomly. A total of 142 patients with UA, 8 with non-ST-elevation myocardial infarction (NSTEMI), and 8 with stable angina (SA) at Nanjing Hospital of Traditional Chinese Medicine Affiliated with Nanjing University of Chinese Medicine from January 2019 to February 2022 were recruited. Fifty-eight healthy volunteers (HVs) were recruited to the control group during the same period. Differentially expressed miRNAs in serum exosomes of UA patients were first identified by high-throughput sequencing, followed by verification via quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Our findings aim to explore their diagnostic potentials in UA, and their biological functions, as well as the correlation between conventional biochemical indexes of UA. RESULTS MiR-127, miR-150, and miR-145 were differentially expressed miRNAs in the serum EVs of 8 UA patients, 8 NSTEMI patients, 8 SA patients, and 8 HVs by high-throughput sequencing, which were downregulated in UA patients versus HVs. Moreover, the relative levels of differentially expressed miRNAs in the serum EVs of the remaining UA patients and HVs were measured by qRT-PCR. The area under the curve of miR-127, miR-150, and miR-145 in distinguishing UA patients from HVs was 0.872, 0.856, and 0.803, respectively. Notably, the area under the curve of the combination of the three differentially expressed miRNAs for diagnosing UA was 0.944. A GO analysis revealed that miR-127, miR-150, and miR-145 were mainly enriched in cell adhesion and migration, whereas KEGG pathway enrichment analysis showed that they were enriched in the PI3K-Akt, MAPK, and Hippo signaling pathways. Multivariable logistic regression analysis identified cardiac troponin I (cTnI) (P=0.0006), miR-127 (P=0.0001), miR-150 (P=0.0004), and miR-145 (P=0.0005) as independent risk factors for UA. Spearman's rank correlation test showed a significant correlation between cTnI and miR-127 (r=0.1988, P=0.0067). CONCLUSIONS MiR-127, miR-150, and miR-145 in serum EVs are closely linked with UA and serve as novel diagnostic biomarkers.
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Affiliation(s)
- Yuan Qu
- Nanjing Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Xia Huang
- Nanjing Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Zhang
- Nanjing Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Xin He
- Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Zhiliang Chen
- Nanjing Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Yajie Zhang
- Nanjing Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Ning Gu
- Nanjing Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
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19
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Nguyen MT, Dash R, Jeong K, Lee W. Role of Actin-Binding Proteins in Skeletal Myogenesis. Cells 2023; 12:2523. [PMID: 37947600 PMCID: PMC10650911 DOI: 10.3390/cells12212523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 11/12/2023] Open
Abstract
Maintenance of skeletal muscle quantity and quality is essential to ensure various vital functions of the body. Muscle homeostasis is regulated by multiple cytoskeletal proteins and myogenic transcriptional programs responding to endogenous and exogenous signals influencing cell structure and function. Since actin is an essential component in cytoskeleton dynamics, actin-binding proteins (ABPs) have been recognized as crucial players in skeletal muscle health and diseases. Hence, dysregulation of ABPs leads to muscle atrophy characterized by loss of mass, strength, quality, and capacity for regeneration. This comprehensive review summarizes the recent studies that have unveiled the role of ABPs in actin cytoskeletal dynamics, with a particular focus on skeletal myogenesis and diseases. This provides insight into the molecular mechanisms that regulate skeletal myogenesis via ABPs as well as research avenues to identify potential therapeutic targets. Moreover, this review explores the implications of non-coding RNAs (ncRNAs) targeting ABPs in skeletal myogenesis and disorders based on recent achievements in ncRNA research. The studies presented here will enhance our understanding of the functional significance of ABPs and mechanotransduction-derived myogenic regulatory mechanisms. Furthermore, revealing how ncRNAs regulate ABPs will allow diverse therapeutic approaches for skeletal muscle disorders to be developed.
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Affiliation(s)
- Mai Thi Nguyen
- Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea; (M.T.N.); (K.J.)
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea;
- Department of New Biology, Daegu Gyeongbuk Institute of Science & Technology (DGIST), Daegu 42988, Republic of Korea
| | - Kyuho Jeong
- Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea; (M.T.N.); (K.J.)
| | - Wan Lee
- Department of Biochemistry, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Republic of Korea; (M.T.N.); (K.J.)
- Channelopathy Research Center, Dongguk University College of Medicine, 32 Dongguk-ro, Ilsan Dong-gu, Goyang 10326, Republic of Korea
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20
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Roshani M, Molavizadeh D, Sadeghi S, Jafari A, Dashti F, Mirazimi SMA, Ahmadi Asouri S, Rajabi A, Hamblin MR, Anoushirvani AA, Mirzaei H. Emerging roles of miR-145 in gastrointestinal cancers: A new paradigm. Biomed Pharmacother 2023; 166:115264. [PMID: 37619484 DOI: 10.1016/j.biopha.2023.115264] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/25/2023] [Accepted: 07/31/2023] [Indexed: 08/26/2023] Open
Abstract
Gastrointestinal (GI) carcinomas are a group of cancers affecting the GI tract and digestive organs, such as the gastric, liver, bile ducts, pancreas, small intestine, esophagus, colon, and rectum. MicroRNAs (miRNAs) are small functional non-coding RNAs (ncRNAs) which are involved in regulating the expression of multiple target genes; mainly at the post-transcriptional level, via complementary binding to their 3'-untranslated region (3'-UTR). Increasing evidence has shown that miRNAs have critical roles in modulating of various physiological and pathological cellular processes and regulating the occurrence and development of human malignancies. Among them, miR-145 is recognized for its anti-oncogenic properties in various cancers, including GI cancers. MiR-145 has been implicated in diverse biological processes of cancers through the regulation of target genes or signaling, including, proliferation, differentiation, tumorigenesis, angiogenesis, apoptosis, metastasis, and therapy resistance. In this review, we have summarized the role of miR-145 in selected GI cancers and also its downstream molecules and cellular processes targets, which could lead to a better understanding of the miR-145 in these cancers. In conclusion, we reveal the potential diagnostic, prognostic, and therapeutic value of miR-145 in GI cancer, and hope to provide new ideas for its application as a biomarker as well as a therapeutic target for the treatment of these cancer.
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Affiliation(s)
- Mohammad Roshani
- Internal Medicine and Gastroenterology, Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Danial Molavizadeh
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sara Sadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sahar Ahmadi Asouri
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for BasicSciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Rajabi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, South Africa
| | - Ali Arash Anoushirvani
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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21
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Burgon PG, Weldrick JJ, Talab OMSA, Nadeer M, Nomikos M, Megeney LA. Regulatory Mechanisms That Guide the Fetal to Postnatal Transition of Cardiomyocytes. Cells 2023; 12:2324. [PMID: 37759546 PMCID: PMC10528641 DOI: 10.3390/cells12182324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 09/29/2023] Open
Abstract
Heart disease remains a global leading cause of death and disability, necessitating a comprehensive understanding of the heart's development, repair, and dysfunction. This review surveys recent discoveries that explore the developmental transition of proliferative fetal cardiomyocytes into hypertrophic postnatal cardiomyocytes, a process yet to be well-defined. This transition is key to the heart's growth and has promising therapeutic potential, particularly for congenital or acquired heart damage, such as myocardial infarctions. Although significant progress has been made, much work is needed to unravel the complex interplay of signaling pathways that regulate cardiomyocyte proliferation and hypertrophy. This review provides a detailed perspective for future research directions aimed at the potential therapeutic harnessing of the perinatal heart transitions.
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Affiliation(s)
- Patrick G. Burgon
- Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar
| | - Jonathan J. Weldrick
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
| | | | - Muhammad Nadeer
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Michail Nomikos
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (O.M.S.A.T.)
| | - Lynn A. Megeney
- Department of Medicine, Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; (J.J.W.); (L.A.M.)
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
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22
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Jiang Y, Zhao Y, Li ZY, Chen S, Fang F, Cai JH. Potential roles of microRNAs and long noncoding RNAs as diagnostic, prognostic and therapeutic biomarkers in coronary artery disease. Int J Cardiol 2023; 384:90-99. [PMID: 37019219 DOI: 10.1016/j.ijcard.2023.03.067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/27/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023]
Abstract
Coronary artery disease (CAD), which is mainly caused by atherosclerotic processes in coronary arteries, became a significant health issue. MicroRNAs (miRNAs), and long noncoding RNAs (lncRNAs), have been shown to be stable in plasma and could thereby be adopted as biomarkers for CAD diagnosis and treatment. MiRNAs can regulate CAD development through different pathways and mechanisms, including modulation of vascular smooth muscle cell (VSMC) activity, inflammatory responses, myocardial injury, angiogenesis, and leukocyte adhesion. Similarly, previous studies have indicated that the causal effects of lncRNAs in CAD pathogenesis and their utility in CAD diagnosis and treatment, has been found to lead to cell cycle transition, proliferation dysregulation, and migration in favour of CAD development. Differential expression of miRNAs and lncRNAs in CAD patients has been identified and served as diagnostic, prognostic and therapeutic biomarkers for the assessment of CAD patients. Thus, in the current review, we summarize the functions of miRNAs and lncRNAs, which aimed to identify novel targets for the CAD diagnosis, prognosis, and treatment.
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Affiliation(s)
- Yong Jiang
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China.
| | - Ying Zhao
- Department of Cardiology, Jilin Central Hospital, Jilin 132011, China
| | - Zheng-Yi Li
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China
| | - Shuang Chen
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China
| | - Fang Fang
- Department of Laboratory Medicine, Jilin Medical University, No. 5 Jilin Street, Jilin 132013, China.
| | - Jian-Hui Cai
- Department of Clinical Medicine, Jilin Medical University, Jilin 132013, China; Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University, Jilin 132013, China.
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23
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Fernández-Villabrille S, Martín-Carro B, Martín-Vírgala J, Alonso-Montes C, Fernández-Fernández A, Martínez-Salgado C, Fernández-Martín JL, Naves-Díaz M, Cannata-Andía JB, Carrillo-López N, Panizo S. Phosphorus May Induce Phenotypic Transdifferentiation of Vascular Smooth Muscle Cells through the Reduction of microRNA-145. Nutrients 2023; 15:2918. [PMID: 37447244 DOI: 10.3390/nu15132918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Phosphorus is a vital element for life found in most foods as a natural component, but it is also one of the most used preservatives added during food processing. High serum phosphorus contributes to develop vascular calcification in chronic kidney disease; however, it is not clear its effect in a population without kidney damage. The objective of this in vivo and in vitro study was to investigate the effect of high phosphorus exposure on the aortic and serum levels of miR-145 and its effect on vascular smooth muscle cell (VSMCs) changes towards less contractile phenotypes. The study was performed in aortas and serum from rats fed standard and high-phosphorus diets, and in VSMCs exposed to different concentrations of phosphorus. In addition, miR-145 silencing and overexpression experiments were carried out. In vivo results showed that in rats with normal renal function fed a high P diet, a significant increase in serum phosphorus was observed which was associated to a significant decrease in the aortic α-actin expression which paralleled the decrease in aortic and serum miR-145 levels, with no changes in the osteogenic markers. In vitro results using VSMCs corroborated the in vivo findings. High phosphorus first reduced miR-145, and afterwards α-actin expression. The miR-145 overexpression significantly increased α-actin expression and partially prevented the increase in calcium content. These results suggest that miR-145 could be an early biomarker of vascular calcification, which could give information about the initiation of the transdifferentiation process in VSMCs.
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Affiliation(s)
- Sara Fernández-Villabrille
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
| | - Beatriz Martín-Carro
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
| | - Julia Martín-Vírgala
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
| | - Cristina Alonso-Montes
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
| | | | - Carlos Martínez-Salgado
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - José L Fernández-Martín
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
| | - Manuel Naves-Díaz
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
- Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Jorge B Cannata-Andía
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
- Department of Medicine, Universidad de Oviedo, 33011 Oviedo, Spain
| | - Natalia Carrillo-López
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
| | - Sara Panizo
- Metabolismo Óseo, Vascular y Enfermedades Inflamatorias Crónicas, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain
- Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS2040, Kidney Disease), 28040 Madrid, Spain
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24
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Mengozzi A, Costantino S, Mongelli A, Mohammed SA, Gorica E, Delfine V, Masi S, Virdis A, Ruschitzka F, Paneni F. Epigenetic Signatures in Arterial Hypertension: Focus on the Microvasculature. Int J Mol Sci 2023; 24:ijms24054854. [PMID: 36902291 PMCID: PMC10003673 DOI: 10.3390/ijms24054854] [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: 01/31/2023] [Revised: 02/25/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress.
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Affiliation(s)
- Alessandro Mengozzi
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
- Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, 56127 Pisa, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Sarah Costantino
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
| | - Alessia Mongelli
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
| | - Shafeeq A. Mohammed
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
| | - Era Gorica
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
| | - Valentina Delfine
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
| | - Stefano Masi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
- Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK
| | - Agostino Virdis
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
| | - Frank Ruschitzka
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
| | - Francesco Paneni
- Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
- Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
- Department of Research and Education, University Hospital Zurich, 8091 Zurich, Switzerland
- Correspondence: or francesco.paneni@uzh; Tel.: +41-44-6355096
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25
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Vazgiourakis VM, Zervou MI, Papageorgiou L, Chaniotis D, Spandidos DA, Vlachakis D, Eliopoulos E, Goulielmos GN. Association of endometriosis with cardiovascular disease: Genetic aspects (Review). Int J Mol Med 2023; 51:29. [PMID: 36799179 PMCID: PMC9943539 DOI: 10.3892/ijmm.2023.5232] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
Cardiovascular disease (CVD) comprises a broad spectrum of pathological conditions that affect the heart or blood vessels, including sequelae that arise from damaged vasculature in other organs of the body, such as the brain, kidneys or eyes. Atherosclerosis is a chronic inflammatory disease of the arterial intima and is the primary cause of coronary artery disease, peripheral vascular disease, heart attack, stroke and renal pathology. It represents a leading cause of mortality worldwide and the loss of human productivity that is marked by an altered immune response. Endometriosis is a heritable, heterogeneous, common gynecological condition influenced by multiple genetic, epigenetic and environmental factors, affecting up to 10% of the female population of childbearing age, causing pain and infertility; it is characterized by the ectopic growth of endometrial tissue outside the uterine cavity. Of note, epidemiological data obtained thus far have suggested a link between endometriosis and the risk of developing CVD. The similarities observed in specific molecular and cellular pathways of endometriosis and CVD may be partially explained by a shared genetic background. The present review presents and discusses the shared genetic factors which have been reported to be associated with the development of both disorders.
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Affiliation(s)
- Vassilios M. Vazgiourakis
- Intensive Care Unit, University Hospital of Larissa, University of Thessaly, Faculty of Medicine, 41110 Larissa, Greece
| | - Maria I. Zervou
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71403 Heraklion, Greece
| | - Louis Papageorgiou
- Department of Biomedical Sciences, School of Health and Care Sciences, University of West Attica, 12243 Athens, Greece
- Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Dimitrios Chaniotis
- Department of Biomedical Sciences, School of Health and Care Sciences, University of West Attica, 12243 Athens, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
| | - Dimitrios Vlachakis
- Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - Elias Eliopoulos
- Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, 11855 Athens, Greece
| | - George N. Goulielmos
- Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, 71403 Heraklion, Greece
- Department of Internal Medicine, University Hospital of Heraklion, 71500 Heraklion, Greece
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26
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Liu J, Wang H, Zeng D, Xiong J, Luo J, Chen X, Chen T, Xi Q, Sun J, Ren X, Zhang Y. The novel importance of miR-143 in obesity regulation. Int J Obes (Lond) 2023; 47:100-108. [PMID: 36528726 DOI: 10.1038/s41366-022-01245-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022]
Abstract
Obesity and substantially increased risk of metabolic diseases have become a global epidemic. microRNAs have attracted a great deal of attention as a potential therapeutic target for obesity. MiR-143 has been known to specifically promote adipocyte differentiation by downregulating extracellular signal-regulated kinase 5. Our latest study found that miR-143 knockout is against diet-induced obesity by promoting brown adipose tissue thermogenesis and inhibiting white adipose tissue adipogenesis. Moreover, LPS- or IL-6-induced inhibition of miR-143 expression in brown adipocytes promotes thermogenesis by targeting adenylate cyclase 9. In this review, we will summarize the expression and functions of miR-143 in different tissues, the influence of obesity on miR-143 in various tissues, the important role of adipose-derived miR-143 in the development of obesity, the role of miR-143 in immune cells and thermoregulation and discuss the potential significance and application prospects of miR-143 in obesity management.
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Affiliation(s)
- Jie Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Huan Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Dewei Zeng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Jiali Xiong
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Xingping Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.,Jiangxi Province Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, 330045, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Jiajie Sun
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China
| | - Xiaohui Ren
- Ocean College of Hebei Agricultural University, Qinhuangdao, 066003, China.
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
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27
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Hwang H, Chang HR, Baek D. Determinants of Functional MicroRNA Targeting. Mol Cells 2023; 46:21-32. [PMID: 36697234 PMCID: PMC9880601 DOI: 10.14348/molcells.2023.2157] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/09/2022] [Accepted: 11/15/2022] [Indexed: 01/27/2023] Open
Abstract
MicroRNAs (miRNAs) play cardinal roles in regulating biological pathways and processes, resulting in significant physiological effects. To understand the complex regulatory network of miRNAs, previous studies have utilized massivescale datasets of miRNA targeting and attempted to computationally predict the functional targets of miRNAs. Many miRNA target prediction tools have been developed and are widely used by scientists from various fields of biology and medicine. Most of these tools consider seed pairing between miRNAs and their mRNA targets and additionally consider other determinants to improve prediction accuracy. However, these tools exhibit limited prediction accuracy and high false positive rates. The utilization of additional determinants, such as RNA modifications and RNA-binding protein binding sites, may further improve miRNA target prediction. In this review, we discuss the determinants of functional miRNA targeting that are currently used in miRNA target prediction and the potentially predictive but unappreciated determinants that may improve prediction accuracy.
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Affiliation(s)
- Hyeonseo Hwang
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea
| | - Hee Ryung Chang
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea
| | - Daehyun Baek
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea
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28
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You J, Wu Q, Xu G, Gu C, Allen E, Zhu T, Chen L. Exosomal MicroRNA Profiling in Vitreous Humor Derived From Pathological Myopia Patients. Invest Ophthalmol Vis Sci 2023; 64:9. [PMID: 36648415 PMCID: PMC9851280 DOI: 10.1167/iovs.64.1.9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Purpose Pathologic myopia (PM) is one of the primary causes of blindness. This study aims to explore the possible relations between the composition of microRNA in vitreous exosomes of patients with PM and the progression of myopic maculopathy. Methods Vitreous humor (VH) samples were collected from patients undergoing retinal surgery. A total of 15 and 12 VH samples were obtained from patients with PM and control, respectively. The PM group was divided into PM-L (G2) and PM-H groups (G3 and G4) in order to explore differentially expressed microRNAs (DEMs) that account for the relatively poor prognosis in G3 and G4 myopic maculopathy. A Weighted Gene Co-Expression Network Analysis (WGCNA) was conducted to find the persistently altered key microRNAs in myopic maculopathy progression. The Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were used. Results High purity exosomes were extracted from the vitreous fluid of patients with PM and control. The top five downregulated DEMs of PM-H versus PM-L can reflect the tendency of deterioration of PM-H myopic maculopathy. MiR-143-3p and miR-145-5p, which were found in WGCNA, may participate in the development of myopic maculopathy. These microRNAs all relate to the insulin resistance pathway. Conclusions This is the first study to explore the relations between the progression of myopic maculopathy and vitreous exosomal microRNAs. Vitreous exosomal miR-143-3p and miR-145-5p can be considered biomarkers for patients with PM, and the vitreous exosomal DEM associated with PM-H may represent alarming signals of myopic maculopathy deterioration.
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Affiliation(s)
- Jie You
- Department of Ophthalmology & Vision Science, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China,Key NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China,Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China
| | - Qiao Wu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China,School of Life Sciences, Fudan University, Shanghai, China
| | - Gezhi Xu
- Department of Ophthalmology & Vision Science, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China,Key NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China,Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China
| | - Chenyang Gu
- Department of Ophthalmology & Vision Science, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China,Key NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China,Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China
| | - Edward Allen
- Institute of Archaeological Science, Fudan University, Shanghai, China
| | - Tianrui Zhu
- University of Washington, Seattle, Washington, United States
| | - Ling Chen
- Department of Ophthalmology & Vision Science, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China,Key NHC Key Laboratory of Myopia (Fudan University), Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China,Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Shanghai Medical School, Fudan University, Shanghai, China
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Darbo E, Pérot G, Darmusey L, Le Guellec S, Leroy L, Gaston L, Desplat N, Thébault N, Merle C, Rochaix P, Valentin T, Ferron G, Chevreau C, Bui B, Stoeckle E, Ranchere-Vince D, Méeus P, Terrier P, Piperno-Neumann S, Collin F, De Pinieux G, Duffaud F, Coindre JM, Blay JY, Chibon F. Distinct Cellular Origins and Differentiation Process Account for Distinct Oncogenic and Clinical Behaviors of Leiomyosarcomas. Cancers (Basel) 2023; 15:cancers15020534. [PMID: 36672483 PMCID: PMC9856933 DOI: 10.3390/cancers15020534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/02/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
In leiomyosarcoma (LMS), a very aggressive disease, a relatively transcriptionally uniform subgroup of well-differentiated tumors has been described and is associated with poor survival. The question raised how differentiation and tumor progression, two apparently antagonist processes, coexist and allow tumor malignancy. We first identified the most transcriptionally homogeneous LMS subgroup in three independent cohorts, which we named 'hLMS'. The integration of multi-omics data and functional analysis suggests that hLMS originate from vascular smooth muscle cells and show that hLMS transcriptional program reflects both modulations of smooth muscle contraction activity controlled by MYOCD/SRF regulatory network and activation of the cell cycle activity controlled by E2F/RB1 pathway. We propose that the phenotypic plasticity of vascular smooth muscle cells coupled with MYOCD/SRF pathway amplification, essential for hLMS survival, concomitant with PTEN absence and RB1 alteration, could explain how hLMS balance this uncommon interplay between differentiation and aggressiveness.
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Affiliation(s)
- Elodie Darbo
- INSERM U1218 ACTION, Institut Bergonié, 33000 Bordeaux, France
- CNRS UMR5800, LaBRI, 33400 Talence, France
- Department of Medical and Biological Sciences, Université de Bordeaux, 33000 Bordeaux, France
| | - Gaëlle Pérot
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Centre Hospitalier Universitaire (CHU) de Toulouse, IUCT-Oncopole, 31000 Toulouse, France
| | - Lucie Darmusey
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
- Department of Medical and Biological Sciences, University of Toulouse 3, 31000 Toulouse, France
| | - Sophie Le Guellec
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Laura Leroy
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Laëtitia Gaston
- Department of Medical Genetics, CHU de Bordeaux, 33000 Bordeaux, France
| | - Nelly Desplat
- INSERM U1218 ACTION, Institut Bergonié, 33000 Bordeaux, France
| | - Noémie Thébault
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Candice Merle
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
- Department of Medical and Biological Sciences, University of Toulouse 3, 31000 Toulouse, France
| | - Philippe Rochaix
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Thibaud Valentin
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Oncology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Gwenaël Ferron
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Surgical Oncology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Christine Chevreau
- Department of Oncology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
| | - Binh Bui
- Department of Oncology, Institut Bergonié, 33000 Bordeaux, France
| | | | | | - Pierre Méeus
- Department of Surgery, Centre Léon Bérard, 69000 Lyon, France
| | - Philippe Terrier
- Department of Pathology, Institut Gustave Roussy, 94800 Villejuif, France
| | | | - Françoise Collin
- Department of Pathology, Centre Georges-François Leclerc, 21000 Dijon, France
| | - Gonzague De Pinieux
- Department of Pathology, Hôpital Universitaire Trousseau, 37170 Tours, France
| | - Florence Duffaud
- Medical Oncology Unit, APHM Hôpital La Timone, Aix Marseille University, 13000 Marseille, France
| | - Jean-Michel Coindre
- INSERM U1218 ACTION, Institut Bergonié, 33000 Bordeaux, France
- Department of Pathology, Institut Bergonié, 33000 Bordeaux, France
| | - Jean-Yves Blay
- Department of Medical Oncology, Centre Léon Bérard, 69000 Lyon, France
- INSERM U1052, CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon 1, 69000 Lyon, France
| | - Frédéric Chibon
- OncoSarc, INSERM U1037, Cancer Research Center in Toulouse (CRCT), 31000 Toulouse, France
- Department of Pathology, Institut Claudius Régaud, IUCT-Oncopole, 31000 Toulouse, France
- Correspondence: ; Tel.: +33-0582741765
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Meng L, Yu X, Han H, Jia X, Hu B, Zhang L, Wang Z, Zhang W, Zhong M, Zhu H. Circulating miR-143 and miR-145 as promising biomarkers for evaluating severity of coronary artery stenosis in patients with acute coronary syndrome. Clin Biochem 2023; 111:32-40. [PMID: 36241060 DOI: 10.1016/j.clinbiochem.2022.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 08/17/2022] [Accepted: 10/07/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Multiple studies have provided evidence that miR-143 and miR-145 play a crucial role in the pathogenesis and progression of atherosclerosis. In the present study, we aim to investigate the expression of plasma miR-143 and miR-145 in patients with acute coronary syndrome (ACS) and their association with the severity of coronary artery stenosis. METHODS The study enrolled 279 patients with ACS, including 201 patients with unstable angina (UA) and 78 patients with acute myocardial infarction (AMI), and 65 matched subjects as the control group. The plasma levels of miR-143 and miR-145 were detected by quantitative real-time PCR (qRT-PCR). Gensini score was applied to evaluate the severity of coronary artery stenosis. RESULTS Plasma levels of miR-143 and miR-145 in patients with ACS were both decreased compared with the control group (p < 0.001). Plasma levels of miR-143 and miR-145 were negatively correlated with Gensini score (miR-143: r = -0.246, p < 0.001; miR-145: r = -0.222, p < 0.001). Logistic regression analysis showed that miR-143 and miR-145 were protective factors for the onset of ACS, UA, or AMI separately. MiR-143 (AUC: 0.786, p < 0.001) and miR-145 (AUC: 0.793, p < 0.001) were able to predict the degree of coronary artery stenosis greater than 50 %. CONCLUSION The plasma levels of miR-143 and miR-145 were significantly decreased in ACS patients and were negatively correlated with coronary stenosis. In conclusion, plasma miR-143 and miR-145 levels can be used as noninvasive biomarkers for evaluating coronary artery stenosis.
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Affiliation(s)
- Linlin Meng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xin Yu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Cardiology, The People's Hospital of Pingyi County, Shandong, China
| | - Haitao Han
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xu Jia
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Boang Hu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Lei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Zhihao Wang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University; Shandong key Laboratory of Cardiovascular Proteomics, Jinan, Shandong, 250012, China
| | - Wei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Ming Zhong
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Hui Zhu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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Li Z, Guo Y, Ndandala CB, Chen H, Huang C, Zhao G, Huang H, Li G, Chen H. Analysis of circRNA and miRNA expression profiles in IGF3-induced ovarian maturation in spotted scat ( Scatophagus argus). Front Endocrinol (Lausanne) 2022; 13:998207. [PMID: 36506051 PMCID: PMC9732426 DOI: 10.3389/fendo.2022.998207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/03/2022] [Indexed: 11/26/2022] Open
Abstract
Insulin-like growth factor 3 (IGF3) induces ovarian maturation in teleosts; however, research on its molecular regulatory mechanism remains deficient. Circular RNAs (circRNAs) and microRNAs (miRNAs) are involved in various biological processes, including reproduction. In this study, circRNAs and miRNAs involved in IGF3-induced ovarian maturation were evaluated in spotted scat (Scatophagus argus). In ovarian tissues, we identified 176 differentially expressed (DE) circRNAs and 52 DE miRNAs between IGF3 treatment and control groups. Gene Ontology (GO) enrichment analyses showed that host genes of DE circRNAs and target genes of DE miRNAs were enriched for various processes with a high degree of overlap, including cellular process, reproduction, reproductive process, biological adhesion, growth, extracellular region, cell junction, catalytic activity, and transcription factor activity. Enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included cell adhesion molecules, ECM-receptor interaction, regulation of actin cytoskeleton, focal adhesion, cell cycle, Hedgehog signaling pathway, phosphatidylinositol signaling system, PI3K-Akt signaling pathway, Apelin signaling pathway, Notch signaling pathway, insulin signaling pathway, and Rap1 signaling pathway. A circRNA-miRNA-mRNA regulatory network was constructed, including DE genes involved in reproduction (e.g., oocyte maturation, oocyte meiosis, and ECM remodeling), such as ccnd2, hecw2, dnm2, irs1, adam12, and cdh13. According to the regulatory network and tissue distribution, we identified one circRNA (Lachesis_group5:6245955|6270787) and three miRNAs (novel_miR_622, novel_miR_980, and novel_miR_64) that may exert regulatory effects in IGF3-induced ovarian maturation in S. argus. Taken together, this study provides a novel insight into the molecular mechanisms by which IGF3 functions in ovaries and highlights the effects of circRNAs and miRNAs in reproduction in S. argus.
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Affiliation(s)
- Zhiyuan Li
- Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Yuwen Guo
- Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Charles Brighton Ndandala
- Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Huadong Chen
- Guangdong Havwii Agriculture Group Co., LTD, Zhanjiang, China
| | | | | | - Hai Huang
- Key Laboratory of Utilization and Conservation for Tropical Marine Bioresources of Ministry of Education, Hainan Key Laboratory for Conservation and Utilization of Tropical Marine Fishery Resources, Yazhou Bay Innovation Institute, Hainan Tropical Ocean University, Sanya, China
| | - Guangli Li
- Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Fisheries College, Guangdong Ocean University, Zhanjiang, China
| | - Huapu Chen
- Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Fisheries College, Guangdong Ocean University, Zhanjiang, China
- Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
- Key Laboratory of Utilization and Conservation for Tropical Marine Bioresources of Ministry of Education, Hainan Key Laboratory for Conservation and Utilization of Tropical Marine Fishery Resources, Yazhou Bay Innovation Institute, Hainan Tropical Ocean University, Sanya, China
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32
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Singh D, Rai V, Agrawal DK. Non-Coding RNAs in Regulating Plaque Progression and Remodeling of Extracellular Matrix in Atherosclerosis. Int J Mol Sci 2022; 23:13731. [PMID: 36430208 PMCID: PMC9692922 DOI: 10.3390/ijms232213731] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/31/2022] [Accepted: 11/05/2022] [Indexed: 11/09/2022] Open
Abstract
Non-coding RNAs (ncRNAs) regulate cell proliferation, migration, differentiation, inflammation, metabolism of clinically important biomolecules, and other cellular processes. They do not encode proteins but are involved in the regulatory network of various proteins that are directly related to the pathogenesis of diseases. Little is known about the ncRNA-associated mechanisms of atherosclerosis and related cardiovascular disorders. Remodeling of the extracellular matrix (ECM) is critical in the pathogenesis of atherosclerosis and related disorders; however, its regulatory proteins are the potential subjects to explore with special emphasis on epigenetic regulatory components. The activity of regulatory proteins involved in ECM remodeling is regulated by various ncRNA molecules, as evident from recent research. Thus, it is important to critically evaluate the existing literature to enhance the understanding of nc-RNAs-regulated molecular mechanisms regulating ECM components, remodeling, and progression of atherosclerosis. This is crucial since deregulated ECM remodeling contributes to atherosclerosis. Thus, an in-depth understanding of ncRNA-associated ECM remodeling may identify novel targets for the treatment of atherosclerosis and other cardiovascular diseases.
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Affiliation(s)
| | | | - Devendra K. Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
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Liu J, Liu J, Zeng D, Wang H, Wang Y, Xiong J, Chen X, Luo J, Chen T, Xi Q, Jiang Q, Zhang Y. miR-143-null Is against Diet-Induced Obesity by Promoting BAT Thermogenesis and Inhibiting WAT Adipogenesis. Int J Mol Sci 2022; 23:13058. [PMID: 36361843 PMCID: PMC9658130 DOI: 10.3390/ijms232113058] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/14/2022] [Accepted: 10/25/2022] [Indexed: 09/29/2023] Open
Abstract
Excessive energy intake is the main cause of obesity, and stimulation of brown adipose tissue (BAT) thermogenesis has emerged as an attractive tool for anti-obesity. Although miR-143 has been reported to promote white adipocyte differentiation, its role in BAT remains unclear. In our study, we found that during HFD-induced obesity, the expression of miR-143 in BAT was significantly reduced, and the expression of miR-143 in WAT first increased and then decreased. Knockout (KO) of miR-143 with CRISPR/Cas9 did not affect the energy metabolism of normal diet fed mice and brown adipocyte differentiation but inhibited the differentiation of white adipocytes. Importantly, during high fat diet-induced obesity, miR-143KO significantly reduced body weight, and improved energy expenditure, insulin sensitivity, and glucose tolerance. Further exploration showed that miR-143KO reduced the weight of adipose tissue, promoted mitochondrial number and functions, induced thermogenesis and lipolysis of BAT, increased lipolysis, and inhibited lipogenesis of white adipose tissue (WAT). Our study considerably improves our collective understanding of the function of miR-143 in adipose tissue and its potential significance in anti-obesity and provides a new avenue for the management of obesity through the inhibition of miR-143 in BAT and WAT.
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Affiliation(s)
- Jie Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Jiatao Liu
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Dewei Zeng
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Huan Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Yun Wang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Jiali Xiong
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Xingping Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
- Jiangxi Province Key Laboratory of Animal Nutrition, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Junyi Luo
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Ting Chen
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Qingyan Jiang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou 510642, China
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Serum microRNAs in Systemic Sclerosis, Associations with Digital Vasculopathy and Lung Involvement. Int J Mol Sci 2022; 23:ijms231810731. [PMID: 36142646 PMCID: PMC9503032 DOI: 10.3390/ijms231810731] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/09/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022] Open
Abstract
Background and aims: Systemic sclerosis (SSc) is an autoimmune, rare multisystem chronic disease that is still not well-understood aetiologically and is challenging diagnostically. In the literature, there are ever-increasing assumptions regarding the epigenetic mechanisms involved in SSc development; one of them is circulating microRNAs. Many of them regulate TLR pathways and are significant in autoimmune balance. The aim of this study was to determine profile expression of selected microRNAs in SSc patients, including miR-126, -132, -143, -145, -155, -181a, -29a and -3148, in comparison to healthy controls. Methods: Serum microRNAs were isolated from 45 patients with SSc and 57 healthy donors (HC). Additionally, SSc patients were considered in the aspect of disease subtype, including diffuse systemic sclerosis (dcSSc) and limited systemic sclerosis (lcSSc). Results: miR-3148 was detected neither in the serum of HC nor in SSc patients. All of the rest of the analyzed microRNAs, excluding miR-126, miR-29a and miR-181a, were significantly upregulated in SSc patients in comparison to HC. However, miR-181a has been revealed only in the serum of patients with lcSSc but not dcSSc. Moderate positive correlations between the transfer factor of the lung for carbon monoxide (TLCO) and miR-126 and miR-145 were observed. A significant correlation has been found between serum miR-143 level and forced vital capacity (FVC). SSc patients with FVC ≤ 70% were characterized by significantly lower levels of miR-143 compared to patients with normal FVC. Additionally, the expression of miR-132 was significantly higher in dcSSc subgroup with detected active lung lesions compared to dcSSc patients with fibrotic lesions. Patients with an early scleroderma pattern of microangiopathy seen on nailfold video-capillaroscopy (NVC) revealed higher expression of miR-155 in serum than those with a late pattern. Conclusions: The expression profile of circulating cell-free miRNAs is significantly changed in the serum of SSc patients compared to healthy individuals. Downregulation of miRNA-181a and overexpression of miR-132, miR-143, miR-145 and miR-155 in serum may be significant in SSc in the context of biomarkers.
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Sufianov A, Begliarzade S, Kudriashov V, Nafikova R, Ilyasova T, Liang Y. Role of miRNAs in vascular development. Noncoding RNA Res 2022; 8:1-7. [PMID: 36262425 PMCID: PMC9552023 DOI: 10.1016/j.ncrna.2022.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 11/27/2022] Open
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Khachigian LM, Black BL, Ferdinandy P, De Caterina R, Madonna R, Geng YJ. Transcriptional regulation of vascular smooth muscle cell proliferation, differentiation and senescence: Novel targets for therapy. Vascul Pharmacol 2022; 146:107091. [PMID: 35896140 DOI: 10.1016/j.vph.2022.107091] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 10/16/2022]
Abstract
Vascular smooth muscle cells (SMC) possess a unique cytoplasticity, regulated by transcriptional, translational and phenotypic transformation in response to a diverse range of extrinsic and intrinsic pathogenic factors. The mature, differentiated SMC phenotype is physiologically typified transcriptionally by expression of genes encoding "contractile" proteins, such as SMα-actin (ACTA2), SM-MHC (myosin-11) and SM22α (transgelin). When exposed to various pathological conditions (e.g., pro-atherogenic risk factors, hypertension), SMC undergo phenotypic modulation, a bioprocess enabling SMC to de-differentiate in immature stages or trans-differentiate into other cell phenotypes. As recent studies suggest, the process of SMC phenotypic transformation involves five distinct states characterized by different patterns of cell growth, differentiation, migration, matrix protein expression and declined contractility. These changes are mediated via the action of several transcriptional regulators, including myocardin and serum response factor. Conversely, other factors, including Kruppel-like factor 4 and nuclear factor-κB, can inhibit SMC differentiation and growth arrest, while factors such as yin yang-1, can promote SMC differentiation whilst inhibiting proliferation. This article reviews recent advances in our understanding of regulatory mechanisms governing SMC phenotypic modulation. We propose the concept that transcription factors mediating this switching are important biomarkers and potential pharmacological targets for therapeutic intervention in cardiovascular disease.
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Affiliation(s)
- Levon M Khachigian
- Vascular Biology and Translational Research, Department of Pathology, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
| | - Brian L Black
- Cardiovascular Research Institute, University of California, San Francisco, CA, United States of America
| | - Péter Ferdinandy
- Cardiovascular and Metabolic Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, 1089 Budapest, Hungary; Pharmahungary Group, 6722 Szeged, Hungary
| | - Raffaele De Caterina
- Cardiovascular Division, Pisa University Hospital & University of Pisa, Via Paradisa, 2, Pisa 56124, Italy
| | - Rosalinda Madonna
- Cardiovascular Division, Pisa University Hospital & University of Pisa, Via Paradisa, 2, Pisa 56124, Italy; Division of Cardiovascular Medicine, Department of Internal Medicine, The Center for Cardiovascular Biology and Atherosclerosis Research, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, United States of America
| | - Yong-Jian Geng
- Division of Cardiovascular Medicine, Department of Internal Medicine, The Center for Cardiovascular Biology and Atherosclerosis Research, McGovern School of Medicine, University of Texas Health Science Center at Houston, Houston, TX, United States of America
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Deshpande A, Shetty PMV, Frey N, Rangrez AY. SRF: a seriously responsible factor in cardiac development and disease. J Biomed Sci 2022; 29:38. [PMID: 35681202 PMCID: PMC9185982 DOI: 10.1186/s12929-022-00820-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 05/27/2022] [Indexed: 11/10/2022] Open
Abstract
The molecular mechanisms that regulate embryogenesis and cardiac development are calibrated by multiple signal transduction pathways within or between different cell lineages via autocrine or paracrine mechanisms of action. The heart is the first functional organ to form during development, which highlights the importance of this organ in later stages of growth. Knowledge of the regulatory mechanisms underlying cardiac development and adult cardiac homeostasis paves the way for discovering therapeutic possibilities for cardiac disease treatment. Serum response factor (SRF) is a major transcription factor that controls both embryonic and adult cardiac development. SRF expression is needed through the duration of development, from the first mesodermal cell in a developing embryo to the last cell damaged by infarction in the myocardium. Precise regulation of SRF expression is critical for mesoderm formation and cardiac crescent formation in the embryo, and altered SRF levels lead to cardiomyopathies in the adult heart, suggesting the vital role played by SRF in cardiac development and disease. This review provides a detailed overview of SRF and its partners in their various functions and discusses the future scope and possible therapeutic potential of SRF in the cardiovascular system.
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Affiliation(s)
- Anushka Deshpande
- Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.,Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Kiel, Germany
| | - Prithviraj Manohar Vijaya Shetty
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Norbert Frey
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
| | - Ashraf Yusuf Rangrez
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany. .,DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
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Pan-cancer analysis of microRNA expression profiles highlights microRNAs enriched in normal body cells as effective suppressors of multiple tumor types: A study based on TCGA database. PLoS One 2022; 17:e0267291. [PMID: 35476804 PMCID: PMC9045663 DOI: 10.1371/journal.pone.0267291] [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: 12/23/2021] [Accepted: 04/05/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) are frequently deregulated in various types of cancer. While antisense oligonucleotides are used to block oncomiRs, delivery of tumour-suppressive miRNAs holds great potential as a potent anti-cancer strategy. Here, we aim to determine, and functionally analyse, miRNAs that are lowly expressed in various types of tumour but abundantly expressed in multiple normal tissues. METHODS The miRNA sequencing data of 14 cancer types were downloaded from the TCGA dataset. Significant differences in miRNA expression between tumor and normal samples were calculated using limma package (R programming). An adjusted p value < 0.05 was used to compare normal versus tumor miRNA expression profiles. The predicted gene targets were obtained using TargetScan, miRanda, and miRDB and then subjected to gene ontology analysis using Enrichr. Only GO terms with an adjusted p < 0.05 were considered statistically significant. All data from wet-lab experiments (cell viability assays and flow cytometry) were expressed as means ± SEM, and their differences were analyzed using GraphPad Prism software (Student's t test, p < 0.05). RESULTS By compiling all publicly available miRNA profiling data from The Cancer Genome Atlas (TCGA) Pan-Cancer Project, we reveal a small set of tumour-suppressing miRNAs (which we designate as 'normomiRs') that are highly expressed in 14 types of normal tissues but poorly expressed in corresponding tumour tissues. Interestingly, muscle-enriched miRNAs (e.g. miR-133a/b and miR-206) and miRNAs from DLK1-DIO3 locus (e.g. miR-381 and miR-411) constitute a large fraction of the normomiRs. Moreover, we define that the CCCGU motif is absent in the oncomiRs' seed sequences but present in a fraction of tumour-suppressive miRNAs. Finally, the gain of function of candidate normomiRs across several cancer cell types indicates that miR-206 and miR-381 exert the most potent inhibition on multiple cancer types in vitro. CONCLUSION Our results reveal a pan-cancer set of tumour-suppressing miRNAs and highlight the potential of miRNA-replacement therapies for targeting multiple types of tumour.
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Hromadnikova I, Kotlabova K, Krofta L. First-Trimester Screening for Fetal Growth Restriction and Small-for-Gestational-Age Pregnancies without Preeclampsia Using Cardiovascular Disease-Associated MicroRNA Biomarkers. Biomedicines 2022; 10:biomedicines10030718. [PMID: 35327520 PMCID: PMC8945808 DOI: 10.3390/biomedicines10030718] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
The goal of the study was to determine the early diagnostical potential of cardiovascular disease-associated microRNAs for prediction of small-for-gestational-age (SGA) and fetal growth restriction (FGR) without preeclampsia (PE). The whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation from singleton Caucasian pregnancies within the period November 2012 to March 2020. The case-control retrospective study, nested in a cohort, involved all pregnancies diagnosed with SGA (n = 37) or FGR (n = 82) without PE and 80 appropriate-for-gestational age (AGA) pregnancies selected with regard to equality of sample storage time. Gene expression of 29 cardiovascular disease-associated microRNAs was assessed using real-time RT-PCR. Upregulation of miR-16-5p, miR-20a-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, and miR-195-5p was observed in SGA or FGR pregnancies at 10.0% false positive rate (FPR). Upregulation of miR-1-3p, miR-20b-5p, miR-126-3p, miR-130b-3p, and miR-499a-5p was observed in SGA pregnancies only at 10.0% FPR. Upregulation of miR-145-5p, miR-342-3p, and miR-574-3p was detected in FGR pregnancies at 10.0% FPR. The combination of four microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-146a-5p, and miR-181a-5p) was able to identify 75.68% SGA pregnancies at 10.0% FPR in early stages of gestation. The detection rate of SGA pregnancies without PE increased 4.67-fold (75.68% vs. 16.22%) when compared with the routine first-trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation. The combination of seven microRNA biomarkers (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) was able to identify 42.68% FGR pregnancies at 10.0% FPR in early stages of gestation. The detection rate of FGR pregnancies without PE increased 1.52-fold (42.68% vs. 28.05%) when compared with the routine first-trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation. Cardiovascular disease-associated microRNAs represent promising early biomarkers with very suitable predictive potential for SGA or FGR without PE to be implemented into the routine screening programs.
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Affiliation(s)
- Ilona Hromadnikova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic;
- Correspondence: ; Tel.: +420-296-511-336
| | - Katerina Kotlabova
- Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic;
| | - Ladislav Krofta
- Institute for the Care of the Mother and Child, Third Faculty of Medicine, Charles University, 147 00 Prague, Czech Republic;
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McCoy MG, Pérez-Cremades D, Belkin N, Peng W, Zhang B, Chen J, Sachan M, Wara AKMK, Zhuang R, Cheng HS, Feinberg MW. A miRNA cassette reprograms smooth muscle cells into endothelial cells. FASEB J 2022; 36:e22239. [PMID: 35235229 DOI: 10.1096/fj.202101872r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/04/2022] [Accepted: 02/16/2022] [Indexed: 11/11/2022]
Abstract
Cellular reprogramming through targeting microRNAs (miRNAs) holds promise for regenerative therapy due to their profound regulatory effects in proliferation, differentiation, and function. We hypothesized that transdifferentiation of vascular smooth muscle cells (SMCs) into endothelial cells (ECs) using a miRNA cassette may provide a novel approach for use in vascular disease states associated with endothelial injury or dysfunction. miRNA profiling of SMCs and ECs and iterative combinatorial miRNA transfections of human coronary SMCs revealed a 4-miRNA cassette consisting of miR-143-3p and miR-145-5p inhibitors and miR-146a-5p and miR-181b-5p mimics that efficiently produced induced endothelial cells (iECs). Transcriptome profiling, protein expression, and functional studies demonstrated that iECs exhibit high similarity to ECs. Injected iECs restored blood flow recovery even faster than conventional ECs in a murine hindlimb ischemia model. This study demonstrates that a 4-miRNA cassette is sufficient to reprogram SMCs into ECs and shows promise as a novel regenerative strategy for endothelial repair.
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Affiliation(s)
- Michael G McCoy
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel Pérez-Cremades
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Physiology, University of Valencia, INCLIVA Biomedical Research Institute, Valencia, Spain
| | - Nathan Belkin
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Wenhui Peng
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bofang Zhang
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jingshu Chen
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Madhur Sachan
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - A K M Khyrul Wara
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Rulin Zhuang
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Henry S Cheng
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mark W Feinberg
- Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Diazzi S, Baeri A, Fassy J, Lecacheur M, Marin-Bejar O, Girard CA, Lefevre L, Lacoux C, Irondelle M, Mounier C, Truchi M, Couralet M, Ohanna M, Carminati A, Berestjuk I, Larbret F, Gilot D, Vassaux G, Marine JC, Deckert M, Mari B, Tartare-Deckert S. Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma. EMBO Mol Med 2022; 14:e15295. [PMID: 35156321 PMCID: PMC8899916 DOI: 10.15252/emmm.202115295] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 12/20/2022] Open
Abstract
Lineage dedifferentiation toward a mesenchymal‐like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti‐fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK‐targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR‐143/‐145 pro‐fibrotic cluster as a driver of this mesenchymal‐like phenotype. Upregulation of the miR‐143/‐145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR‐143‐3p and miR‐145‐5p, collaborated to mediate transition toward a drug‐resistant undifferentiated mesenchymal‐like state by targeting Fascin actin‐bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA‐mediated regulatory network that contributes to non‐genetic adaptive drug resistance and provides proof of principle that preventing MAPKi‐induced pro‐fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.
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Affiliation(s)
- Serena Diazzi
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Alberto Baeri
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Julien Fassy
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Margaux Lecacheur
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Oskar Marin-Bejar
- Laboratory For Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.,Department of Oncology, KU Leuven, Leuven, Belgium
| | - Christophe A Girard
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Lauren Lefevre
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Caroline Lacoux
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | | | - Carine Mounier
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France.,CYU Université, ERRMECe (EA1391), Neuville-sur-Oise, France
| | - Marin Truchi
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Marie Couralet
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Mickael Ohanna
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Alexandrine Carminati
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Ilona Berestjuk
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Frederic Larbret
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - David Gilot
- INSERM U1242, University of Rennes, Rennes, France
| | - Georges Vassaux
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Jean-Christophe Marine
- Laboratory For Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.,Department of Oncology, KU Leuven, Leuven, Belgium
| | - Marcel Deckert
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Bernard Mari
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France.,FHU-OncoAge, Nice, France
| | - Sophie Tartare-Deckert
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France.,FHU-OncoAge, Nice, France
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Jiang H, Gong R, Wu Y. miR‑129‑5p inhibits oxidized low‑density lipoprotein‑induced A7r5 cell viability and migration by targeting HMGB1 and the PI3k/Akt signaling pathway. Exp Ther Med 2022; 23:243. [PMID: 35222720 PMCID: PMC8815026 DOI: 10.3892/etm.2022.11168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 08/17/2021] [Indexed: 11/28/2022] Open
Abstract
The mechanisms underlying gene therapy for the treatment of cardiovascular diseases remain to be elucidated. microRNAs (miRs) have been recognized as key regulators in vascular smooth muscle cells, which are involved in the formation of atherosclerosis. The present study aimed to explore the role of miR-129-5p in the regulation of high-mobility group box 1 protein (HMGB1) and the PI3k/Akt signaling pathway, and further explore the role of miR-129-5p in the viability and migration of A7r5 cells induced by oxidized low-density lipoprotein (ox-LDL). Cell viability, viability and migration were determined using Cell Counting Kit-8, colony formation, wound healing and Transwell assays. The expression levels of miR-129-5p and HMGB1 were detected using reverse transcription-quantitative PCR and western blotting. A dual-luciferase assay was used to confirm the association between miR-129-5p and HMGB1. RT-qPCR results in the present study demonstrated that the expression levels of miR-129-5p in A7r5 cells induced by ox-LDL were significantly decreased, compared with the control cells. Moreover, the viability and migration of A7r5 cells induced by ox-LDL were increased compared with control group. Western blot and RT-qPCR results showed that miR-129-5p decreased the expression of HMGB1 in A7r5 cells compared with control group. The present results demonstrated that miR-129-5p inhibited the viability, viability and migration of A7r5 cells induced by ox-LDL, and directly targeted HMGB1 to regulate the PI3k/Akt signaling pathway. In conclusion, miR-129-5p inhibited the PI3k/Akt signaling pathway by directly targeting HMGB1, and reduced the viability, viability and migration of A7r5 cells induced by ox-LDL.
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Affiliation(s)
- Hongfei Jiang
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ren Gong
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yanqing Wu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Abdominal Aortic Aneurysm Formation with a Focus on Vascular Smooth Muscle Cells. Life (Basel) 2022; 12:life12020191. [PMID: 35207478 PMCID: PMC8880357 DOI: 10.3390/life12020191] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 12/29/2022] Open
Abstract
Abdominal aortic aneurysm (AAA) is a lethal degenerative vascular disease that affects, mostly, the elder population, with a high mortality rate (>80%) upon rupture. It features a dilation of the aortic diameter to larger than 30 mm or more than 50%. Diverse pathological processes are involved in the development of AAA, including aortic wall inflammation, elastin breakdown, oxidative stress, smooth muscle cell (SMC) phenotypic switching and dysfunction, and extracellular matrix degradation. With open surgery being the only therapeutic option up to date, the lack of pharmaceutical treatment approach calls for identifying novel and effective targets and further understanding the pathological process of AAA. Both lifestyle and genetic predisposition have an important role in increasing the risk of AAA. Several cell types are closely related to the pathogenesis of AAA. Among them, vascular SMCs (VSMCs) are gaining much attention as a critical contributor for AAA initiation and/or progression. In this review, we summarize what is known about AAA, including the risk factors, the pathophysiology, and the established animal models of AAA. In particular, we focus on the VSMC phenotypic switching and dysfunction in AAA formation. Further understanding the regulation of VSMC phenotypic changes may provide novel therapeutic targets for the treatment or prevention of AAA.
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Mangum K, Gallagher K, Davis FM. The Role of Epigenetic Modifications in Abdominal Aortic Aneurysm Pathogenesis. Biomolecules 2022; 12:biom12020172. [PMID: 35204673 PMCID: PMC8961599 DOI: 10.3390/biom12020172] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/30/2021] [Accepted: 01/01/2022] [Indexed: 02/06/2023] Open
Abstract
Abdominal aortic aneurysm (AAA) is a life-threatening disease associated with high morbidity and mortality in the setting of acute rupture. Recently, advances in surgical and endovascular repair of AAA have been achieved; however, pharmaceutical therapies to prevent AAA expansion and rupture remain lacking. This highlights an ongoing need to improve the understanding the pathological mechanisms that initiate formation, maintain growth, and promote rupture of AAA. Over the past decade, epigenetic modifications, such as DNA methylation, posttranslational histone modifications, and non-coding RNA, have emerged as important regulators of cellular function. Accumulating studies reveal the importance of epigenetic enzymes in the dynamic regulation of key signaling pathways that alter cellular phenotypes and have emerged as major intracellular players in a wide range of biological processes. In this review, we discuss the roles and implications of epigenetic modifications in AAA animal models and their relevance to human AAA pathology.
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Shi J, Wei L. Rho Kinases in Embryonic Development and Stem Cell Research. Arch Immunol Ther Exp (Warsz) 2022; 70:4. [PMID: 35043239 PMCID: PMC8766376 DOI: 10.1007/s00005-022-00642-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022]
Abstract
The Rho-associated coiled-coil containing kinases (ROCKs or Rho kinases) belong to the AGC (PKA/PKG/PKC) family of serine/threonine kinases and are major downstream effectors of small GTPase RhoA, a key regulator of actin-cytoskeleton reorganization. The ROCK family contains two members, ROCK1 and ROCK2, which share 65% overall identity and 92% identity in kinase domain. ROCK1 and ROCK2 were assumed to be functionally redundant, based largely on their major common activators, their high degree kinase domain homology, and study results from overexpression with kinase constructs or chemical inhibitors. ROCK signaling research has expanded to all areas of biology and medicine since its discovery in 1996. The rapid advance is befitting ROCK’s versatile functions in modulating various cell behavior, such as contraction, adhesion, migration, proliferation, polarity, cytokinesis, and differentiation. The rapid advance is noticeably driven by an extensive linking with clinical medicine, including cardiovascular abnormalities, aberrant immune responsive, and cancer development and metastasis. The rapid advance during the past decade is further powered by novel biotechnologies including CRISPR-Cas and single cell omics. Current consensus, derived mainly from gene targeting and RNA interference approaches, is that the two ROCK isoforms have overlapping and distinct cellular, physiological and pathophysiology roles. In this review, we present an overview of the milestone discoveries in ROCK research. We then focus on the current understanding of ROCK signaling in embryonic development, current research status using knockout and knockin mouse models, and stem cell research.
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Affiliation(s)
- Jianjian Shi
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, School of Medicine, Indiana University, 1044 West Walnut Street, R4-370, Indianapolis, IN, 46202-5225, USA.
| | - Lei Wei
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, School of Medicine, Indiana University, 1044 West Walnut Street, R4-370, Indianapolis, IN, 46202-5225, USA.
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Marson D, Aulic S, Fermeglia A, Laurini E, Pricl S. Nanovesicles for the delivery of cardiovascular drugs. APPLICATIONS OF NANOVESICULAR DRUG DELIVERY 2022:341-369. [DOI: 10.1016/b978-0-323-91865-7.00009-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Dong K, Shen J, He X, Hu G, Wang L, Osman I, Bunting KM, Dixon-Melvin R, Zheng Z, Xin H, Xiang M, Vazdarjanova A, Fulton DJR, Zhou J. CARMN Is an Evolutionarily Conserved Smooth Muscle Cell-Specific LncRNA That Maintains Contractile Phenotype by Binding Myocardin. Circulation 2021; 144:1856-1875. [PMID: 34694145 PMCID: PMC8726016 DOI: 10.1161/circulationaha.121.055949] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Vascular homeostasis is maintained by the differentiated phenotype of vascular smooth muscle cells (VSMCs). The landscape of protein coding genes comprising the transcriptome of differentiated VSMCs has been intensively investigated but many gaps remain including the emerging roles of noncoding genes. METHODS We reanalyzed large-scale, publicly available bulk and single-cell RNA sequencing datasets from multiple tissues and cell types to identify VSMC-enriched long noncoding RNAs. The in vivo expression pattern of a novel smooth muscle cell (SMC)-expressed long noncoding RNA, Carmn (cardiac mesoderm enhancer-associated noncoding RNA), was investigated using a novel Carmn green fluorescent protein knock-in reporter mouse model. Bioinformatics and quantitative real-time polymerase chain reaction analysis were used to assess CARMN expression changes during VSMC phenotypic modulation in human and murine vascular disease models. In vitro, functional assays were performed by knocking down CARMN with antisense oligonucleotides and overexpressing Carmn by adenovirus in human coronary artery SMCs. Carotid artery injury was performed in SMC-specific Carmn knockout mice to assess neointima formation and the therapeutic potential of reversing CARMN loss was tested in a rat carotid artery balloon injury model. The molecular mechanisms underlying CARMN function were investigated using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. RESULTS We identified CARMN, which was initially annotated as the host gene of the MIR143/145 cluster and recently reported to play a role in cardiac differentiation, as a highly abundant and conserved, SMC-specific long noncoding RNA. Analysis of the Carmn GFP knock-in mouse model confirmed that Carmn is transiently expressed in embryonic cardiomyocytes and thereafter becomes restricted to SMCs. We also found that Carmn is transcribed independently of Mir143/145. CARMN expression is dramatically decreased by vascular disease in humans and murine models and regulates the contractile phenotype of VSMCs in vitro. In vivo, SMC-specific deletion of Carmn significantly exacerbated, whereas overexpression of Carmn markedly attenuated, injury-induced neointima formation in mouse and rat, respectively. Mechanistically, we found that Carmn physically binds to the key transcriptional cofactor myocardin, facilitating its activity and thereby maintaining the contractile phenotype of VSMCs. CONCLUSIONS CARMN is an evolutionarily conserved SMC-specific long noncoding RNA with a previously unappreciated role in maintaining the contractile phenotype of VSMCs and is the first noncoding RNA discovered to interact with myocardin.
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Affiliation(s)
- Kunzhe Dong
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Jian Shen
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Xiangqin He
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Guoqing Hu
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Liang Wang
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Islam Osman
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Kristopher M. Bunting
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Rachael Dixon-Melvin
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Zeqi Zheng
- Department of Cardiology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Hongbo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, 330031, China
- School of Life Sciences, Nanchang University, Nanchang, Jiangxi, 330031, China
| | - Meixiang Xiang
- Department of Cardiology, The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Almira Vazdarjanova
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - David J. R. Fulton
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Jiliang Zhou
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia, 30912, USA
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Liu C, Zhang J, Lun X, Li L. LncRNA PVT1 Promotes Hypoxia-Induced Cardiomyocyte Injury by Inhibiting miR-214-3p. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4604883. [PMID: 34820454 PMCID: PMC8608544 DOI: 10.1155/2021/4604883] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 01/02/2023]
Abstract
OBJECTIVE To explore the effect and related mechanism of LncRNA PVT1 on hypoxia-induced cardiomyocyte injury. METHODS PVT1RNA and miR-214-3p levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell vitality and apoptosis were, respectively, evaluated by Cell Counting Kit-8 (CCK-8) and flow cytometry analysis. Starbase and Dual luciferase reporter (DLR) gene assay was employed to validate the interaction between miR-214-3p and PVT1. RESULTS PVT1 was statistically upregulated, and miR-214-3p was statistically downregulated in hypoxia-induced H9c2 cells. The survival rate of H9c2 cells induced by hypoxia decreased statistically, while the apoptosis rate increased statistically (P < 0.05). PVT1 knockdown upregulated the hypoxia-induced H9c2 cell viability and inhibited apoptosis. DLR assay verified the targeting relationship between PVT1 and miR-214-3p. In addition, miR-214-3p inhibitors reversed the viability of H9c2 cells with PVT1 knockout and promoted apoptosis. CONCLUSION Silencing PVT1 can enhance the hypoxia-induced H9c2 cell viability and inhibit apoptosis, providing a potential target for the treatment of cardiovascular diseases.
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Affiliation(s)
- Chuanliang Liu
- The First Department of Health Care, Weifang People's Hospital, China
| | - Jieqiong Zhang
- The Third Department of Health Care of Weifang People's Hospital, 151 Guangwen Street, Kuiwen District, Weifang City, 261041 Shandong Province, China
| | - Xuejie Lun
- Department of Internal Medicine, Weifang Municipal Hospital, China
| | - Lei Li
- The Third Department of Health Care of Weifang People's Hospital, 151 Guangwen Street, Kuiwen District, Weifang City, 261041 Shandong Province, China
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H3K4 di-methylation governs smooth muscle lineage identity and promotes vascular homeostasis by restraining plasticity. Dev Cell 2021; 56:2765-2782.e10. [PMID: 34582749 PMCID: PMC8567421 DOI: 10.1016/j.devcel.2021.09.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 07/09/2021] [Accepted: 08/30/2021] [Indexed: 12/15/2022]
Abstract
Epigenetic mechanisms contribute to the regulation of cell differentiation and function. Vascular smooth muscle cells (SMCs) are specialized contractile cells that retain phenotypic plasticity even after differentiation. Here, by performing selective demethylation of histone H3 lysine 4 di-methylation (H3K4me2) at SMC-specific genes, we uncovered that H3K4me2 governs SMC lineage identity. Removal of H3K4me2 via selective editing in cultured vascular SMCs and in murine arterial vasculature led to loss of differentiation and reduced contractility due to impaired recruitment of the DNA methylcytosine dioxygenase TET2. H3K4me2 editing altered SMC adaptative capacities during vascular remodeling due to loss of miR-145 expression. Finally, H3K4me2 editing induced a profound alteration of SMC lineage identity by redistributing H3K4me2 toward genes associated with stemness and developmental programs, thus exacerbating plasticity. Our studies identify the H3K4me2-TET2-miR145 axis as a central epigenetic memory mechanism controlling cell identity and function, whose alteration could contribute to various pathophysiological processes.
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50
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Hall IF, Climent M, Viviani Anselmi C, Papa L, Tragante V, Lambroia L, Farina FM, Kleber ME, März W, Biguori C, Condorelli G, Elia L. rs41291957 controls miR-143 and miR-145 expression and impacts coronary artery disease risk. EMBO Mol Med 2021; 13:e14060. [PMID: 34551209 PMCID: PMC8495461 DOI: 10.15252/emmm.202114060] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 01/25/2023] Open
Abstract
The role of single nucleotide polymorphisms (SNPs) in the etiopathogenesis of cardiovascular diseases is well known. The effect of SNPs on disease predisposition has been established not only for protein coding genes but also for genes encoding microRNAs (miRNAs). The miR-143/145 cluster is smooth muscle cell-specific and implicated in the pathogenesis of atherosclerosis. Whether SNPs within the genomic sequence of the miR-143/145 cluster are involved in cardiovascular disease development is not known. We thus searched annotated sequence databases for possible SNPs associated with miR-143/145. We identified one SNP, rs41291957 (G > A), located -91 bp from the mature miR-143 sequence, as the nearest genetic variation to this miRNA cluster, with a minor allele frequency > 10%. In silico and in vitro approaches determined that rs41291957 (A) upregulates miR-143 and miR-145, modulating phenotypic switching of vascular smooth cells towards a differentiated/contractile phenotype. Finally, we analysed association between rs41291957 and CAD in two cohorts of patients, finding that the SNP was a protective factor. In conclusion, our study links a genetic variation to a pathological outcome through involvement of miRNAs.
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Affiliation(s)
- Ignacio Fernando Hall
- Humanitas Research Hospital‐IRCCSRozzanoItaly
- Institute of Genetics and Biomedical ResearchNational Research CouncilRozzanoItaly
| | | | | | - Laura Papa
- Humanitas Research Hospital‐IRCCSRozzanoItaly
| | - Vinicius Tragante
- Department of CardiologyDivision Heart and LungsUniversity Medical Center UtrechtUtrecht UniversityUtrechtThe Netherlands
| | - Luca Lambroia
- Humanitas Research Hospital‐IRCCSRozzanoItaly
- Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
| | - Floriana Maria Farina
- Humanitas Research Hospital‐IRCCSRozzanoItaly
- Institute for Cardiovascular Prevention (IPEK)Ludwig‐Maximillians‐Universität (LMU) MünchenMunichGermany
- Department of Medical Biotechnology and Translational MedicineUniversity of MilanMilanItaly
| | - Marcus E Kleber
- V Department of MedicineMedical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Winfried März
- V Department of MedicineMedical Faculty MannheimHeidelberg UniversityMannheimGermany
- SYNLAB AcademySYNLAB Holding Deutschland GmbHAugsburg and MannheimGermany
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University GrazGrazAustria
| | - Carlo Biguori
- Interventional Cardiology UnitMediterranea CardiocentroNaplesItaly
| | - Gianluigi Condorelli
- Humanitas Research Hospital‐IRCCSRozzanoItaly
- Institute of Genetics and Biomedical ResearchNational Research CouncilRozzanoItaly
- Department of Biomedical SciencesHumanitas UniversityPieve EmanueleItaly
| | - Leonardo Elia
- Humanitas Research Hospital‐IRCCSRozzanoItaly
- Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
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