MiR-128-3p inhibits vascular smooth muscle cell proliferation and migration by repressing FOXO4/MMP9 signaling pathway
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Molecular Medicine
Open Access
RESEARCH ARTICLE
MiR‑128‑3p inhibits vascular smooth muscle cell proliferation and migration by repressing FOXO4/MMP9 signaling pathway Chuan Qu , Xin Liu, Yan Guo, Yuhong Fo, Xiuhuan Chen, Jining Zhou and Bo Yang*
Abstract Background: MicroRNAs (miRNAs) have been identified as important participants in the development of atherosclerosis (AS). The present study explored the role of miR-128-3p in the dysfunction of vascular smooth muscle cells (VSMCs) and the underlying mechanism. Methods: Human VSMCs and ApoE knockout (ApoE−/−) C57BL/6J mice were used to establish AS cell and animal models, respectively. Expression levels of miR-128-3p, forkhead box O4 (FOXO4) and matrix metallopeptidase 9 (MMP9) were detected using qRT-PCR and Western blot, respectively. CCK-8, BrdU, and Transwell assays as well as flow cytometry analysis were performed to detect the proliferation, migration and apoptosis of VSMCs. Levels of inflammatory cytokines and lipids in human VSMCs, mice serum and mice VSMCs were also determined. The binding site between miR-128-3p and 3′UTR of FOXO4 was confirmed using luciferase reporter gene assay. Results: MiR-128-3p was found to be decreased in AS patient serum, ox-LDL-treated VSMCs, AS mice serum and VSMCs of AS mice. Transfection of miR-128-3p mimics suppressed the proliferation and migration of VSMCs, accompanied by the promoted apoptosis and the decreased levels of inflammatory cytokines. Further experiments confirmed the interaction between miR-128-3p and FOXO4. Augmentation of FOXO4 or MMP9 reversed the effects of miR-128-3p. Besides, miR-128-3p inhibited triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) but increased high-density lipoprotein cholesterol (HDL-C) in the serum of AS mice. Conclusion: MiR-128-3p repressed the proliferation and migration of VSMCs through inhibiting the expressions of FOXO4 and MMP9. Keywords: MiR-128-3p, FOXO4, MMP9, Vascular smooth muscle cell, Atherosclerosis Introduction Atherosclerosis (AS) is an inflammatory vascular disease, which contributes to the pathogenesis of a variety of cardiovascular diseases (CVD) (Gholipour et al. 2018). CVD remains the cause of about one third of mortality in the world (Moss and Ramji 2016). However, presently, the early diagnosis of AS is still difficult (Bejarano et al. 2018), and the treatment aims at repressing the levels of *Correspondence: [email protected] Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Jiefang Road No.238, Wuhan 430060, Hubei, China
blood lipids, which has no direct effect on the formation of AS plaques (Orekhov and Ivanova 2016). The development of AS is elicited by inflammation and the dysfunction of vascular smooth muscle cells (VSMCs) (Paone et al. 2019). After vascular injury, VSMCs undergo phenotype-switching, followed by the release of inflammatory factors and the abnormal proliferation and migration, contributing to the formation of AS plaques; receptors such as LOX-1 on the cell membrane
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