Abstract
OBJECTIVE: We aimed to investigate how microRNA-138-5p (miR-138-5p) promotes heart failure (HF) in rats by inhibiting enhancer of zeste homolog 2 (EZH2) and reducing histone methylation in the myeloid differentiation primary response gene 88 (MyD88) promoter region. METHODS: An HF rat model and isoproterenol (ISO)-induced H9c2 cell injury model were established. Echocardiography was used to assess cardiac function in the rats, flow cytometry was used to detect cardiomyocyte apoptosis, and reverse transcription quantitative polymerase chain reaction or Western blotting was performed to detect the expressions of miR-138-5p, EZH2, and Myd88, as well as Bax, Bcl-2, and Caspase-3. The relationship between miR-138-5p and EZH2 was analyzed by luciferase reporter assay. The methylation level of histone H3 lysine 27 trimethylation (H3K27me3) at the Myd88 promoter region mediated by EZH2 was assessed by chromatin immunoprecipitation assay. RESULTS: The expression of miR-138-5p was increased in myocardial tissue in the HF rats and ISO-induced H9c2 cells. Inhibition of miR-138-5p enhanced cardiac function in the HF rats. Inhibiting miR-138-5p decreased cardiomyocyte apoptosis, downregulated the expressions of Bax and Caspase-3 genes, and upregulated the expression of Bcl-2. miR-138-5p targeted and bound to the 3'-untranslated region of EZH2 mRNA, and promoted cardiomyocyte apoptosis by inhibiting EZH2 expression. EZH2 increased the H3K27me3 methylation level in the Myd88 promoter region, leading to decreased Myd88 expression. Overexpression of Myd88 and high EZH2 expression promoted cardiomyocyte apoptosis. CONCLUSIONS: miR-138-5p targets and inhibits the expression of the EZH2 gene, reducing H3K27me3 methylation in the Myd88 promoter region, thereby enhancing Myd88 expression, promoting cardiomyocyte apoptosis, and exacerbating HF.