MiR-141-5p suppresses vascular smooth muscle cell inflammation, proliferation, and migration via inhibiting the HMGB1/NF-κB pathway.

Abstract

MicroRNAs (miRNAs) have been identified as significant modulators in the pathogenesis of atherosclerosis (AS). Additionally, the dysregulation of vascular smooth muscle cells (VSMCs) is a crucial biological event during AS. Our study aimed to explore the functional roles and molecular mechanisms of miR-141-5p in VSMCs dysfunction. C57BL/6 mice were used to establish AS animal model. Human VSMCs were treated by oxidized low-density lipoprotein (ox-LDL) to establish AS cell model. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to probe miR-141-5p and high-mobility group box 1 (HMGB1) mRNA expressions in VSMCs or plasma samples of the mice. Inflammatory cytokines were detected by enzyme-linked immunosorbent assay kits. Cell counting kit-8 and bromodeoxyuridine assays were performed to evaluate cell proliferation. Cell migration and apoptosis were detected with Transwell assay and flow cytometry analysis, respectively. The target gene of miR-141-5p was predicted with the TargetScan database, and the interaction between miR-141-5p and HMGB1/nuclear factor-κB (NF-κB) was further validated by dual-luciferase reporter assay, qRT-PCR, and Western blot analysis. miR-141-5p was found to be decreased in the plasma of patients and mice model with AS. Its expression was also downregulated in VSMCs treated by ox-LDL. miR-141-5p overexpression inhibited the inflammation, proliferation, migration of VSMCs, and promoted the apoptosis of VSMCs. HMGB1 was identified as a direct target of miR-141-5p, and miR-141-5p could repress the activity of HMGB1/NF-κB signaling. HMGB1 restoration reversed the effects of miR-141-5p, and NF-κB inhibitor JSH-23 showed similar effects with miR-141-5p mimics. miR-141-5p inhibits VSMCs' dysfunction by targeting the HMGB1/NF-κB pathway, which probably functions as a protective factor during the development of AS.