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. 2021 Jan;73(1):238-251.
doi: 10.1002/iub.2423. Epub 2020 Dec 17.

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA-139-5p methylation and signal transducer and activator of transcription 1 expression

Xuwei Zheng  1 , Xiaoyan Zhao  1 , Zhanying Han  1 , Kui Chen  1
Affiliations
Free article

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA-139-5p methylation and signal transducer and activator of transcription 1 expression

Xuwei Zheng et al. IUBMB Life. 2021 Jan.
Free article

Abstract

Atherosclerosis (AS) is the main cause of coronary heart disease, in which enhancer of zeste homolog 2 (EZH2) has been implied to participate in this process. Thus, this work proposed to explore the effect of EZH2 on AS from microRNA-139-5p (miR-139-5p)/signal transducer and activator of transcription 1 (STAT1) axis. EZH2, miR-139-5p, and STAT1 expression in arterial tissues of AS patients were detected. Human arterial smooth muscle cells (HASMCs) induced with oxidized low-density lipoprotein (ox-LDL) and the mice fed with high fat diet were treated with silenced EZH2 or upregulated miR-139-5p to explore their roles in proliferation and apoptosis of HASMCs, together with inflammation response and oxidative stress of mice. Chromatin immunoprecipitation experiment was applied to verify the regulatory effect of EZH2 on miR-139-5p through methylation of H3K27me3. The targeting relationship between miR-139-5p and STAT1 was verified by online website and luciferase activity assay. Reduced miR-139-5p and overexpressed EHZ2 and STAT1 were found in AS. Silenced EZH2 or elevated miR-139-5p decreased the production of cholesterol and inhibited inflammation reaction in serum of mice with AS. Silenced EZH2 or elevated miR-139-5p facilitated proliferation and restrained apoptosis of ox-LDL-treated HASMCs, and restrained oxidative stress and cell apoptosis in arterial tissues of AS mice. EZH2 regulated miR-139-5p through H3K27me3, and miR-139-5p targeted STAT1. miR-139-5p silencing antagonized the effects of EZH2 down-regulation on AS. This study manifests that down-regulated EZH2 or elevated miR-139-5p inhibits ox-LDL-induced HASMCs apoptosis, plaque formation, and inflammatory response in AS mice, which may be related to down-regulated STAT1.

Keywords: MicroRNA-139-5p; apoptosis; atherosclerosis; enhancer of zeste homolog 2; methylation; signal transducer and activator of transcription 1.

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