MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor

Abstract

Background/Aims: Increasing evidence links microRNAs to the pathogenesis of peripheral vascular disease. We recently found microRNA-125b (miR-125b) to be one of the most significantly down-regulated microRNAs in human arteries with arteriosclerosis obliterans (ASO) of the lower extremities. However, its function in the process of ASO remains unclear. This study aimed to investigate the expression, regulatory mechanisms, and functions of miR125b in the process of ASO. Methods: Using the tissue explants adherent method, vascular smooth muscle cells (VSMCs) were prepared for this study. A rat carotid artery balloon injury model was constructed to simulate the development of vascular neointima, and a lentiviral transduction system was used to overexpress serum response factor (SRF) or miR-125b. Quantitative real-time PCR (qRT-PCR) was used to detect the expression levels of miR-125b and SRF mRNA. Western blotting was performed to determine the expression levels of SRF and Ki67. In situ hybridization analysis was used to analyze the location and expression levels of miR-125b. CCK-8 and EdU assays were used to assess cell proliferation, and transwell and wound closure assays were performed to measure cell migration. Flow cytometry was used to evaluate cell apoptosis, and a dual-luciferase reporter assay was conducted to examine the effects of miR-125b on SRF. Immunohistochemistry and immunofluorescence analyses were performed to analyze the location and expression levels of SRF and Ki67. Results: miR125b expression was decreased in ASO arteries and platelet-derived growth factor (PDGF)-BB-stimulated VSMCs. miR-125b suppressed VSMC proliferation and migration but promoted VSMC apoptosis. SRF was determined to be a direct target of miR-125b. Exogenous miR-125b expression modulated SRF expression and inhibited vascular neointimal formation in ballooninjured rat carotid arteries. Conclusions: These findings demonstrate a specific role of the miR-125b/SRF pathway in regulating VSMC function and suggest that modulating miR-125b levels might be a novel approach for treating ASO.

MicroRNA‐125b in vascular diseases: An updated systematic review of pathogenetic implications and clinical applications

“…A total of 158 published articles were retrieved during the study period. After applying the exclusion criteria, 35 articles were finally included with full text reviewed (Figure ) . If aligned based on the date of publication, it was observed that the number of studies addressing miR‐125b and vascular diseases increases gradually over time since the first report that was published in 2010 (Figure ).…”

“…In VSMCs from atherosclerotic mice, Cao et al observed that miR‐125b levels decreased after homocysteine‐induced VSMC proliferation, and miR‐125b silenced p53 via DNA methylation by targeting DNMT3b in vitro and in vivo. MiR‐125b has been shown to suppress VSMC proliferation and migration, and mice with experimental carotid artery injury exhibited less neo‐intimal formation and a lower degree of injury after miR‐125b transfection . A more recent study elucidates the role of exosome‐mediated transfer of miR‐125b in vascular disease; Wang et al showed that VSMCs might internalize extracellular vesicles containing miR‐125b, which suppressed myosin 1E expression in these cells and ameliorated the severity of intimal hyperplasia.…”

MicroRNA-125a-3p affects smooth muscle cell function in vascular stenosis

“…Recently, many elements have been confirmed by scientists to play a critical role in the development of VSMC function and arteriosclerosis, such as miR-125b, miR-145, miR-21, miR-206, etc. [46][47][48][49]. Because miR-125a-3p has a significant impact on the cellular events of VSMCs in vitro, we hypothesized that miR-125a-3p has a high probability of playing a significant role in the process of vascular stenosis in vivo.…”

Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis

“…MiR‐451 and miR‐125, as anti‐inflammatory factors, can reduce atherosclerotic plaque formation by modulating VSMC proliferation and inflammation. A hybrid study on laboratory animals and human clinical specimens demonstrated that miR‐451 and miR‐125 could suppress the neointimal formation in injured arteries . MiR‐451 and miR‐125b may also be useful clinical biomarkers for the early diagnosis of coronary plaque rupture .…”

“…A hybrid study on laboratory animals and human clinical specimens demonstrated that miR‐451 and miR‐125 could suppress the neointimal formation in injured arteries . MiR‐451 and miR‐125b may also be useful clinical biomarkers for the early diagnosis of coronary plaque rupture . Overexpression of miR‐22 significantly repressed MCP‐1 expression in peripheral blood mononuclear cells of patients with CAD .…”