Targeting miR-30d reverses pathological cardiac hypertrophy

作者：Jin Li, Zhao Sha, Xiaolan Zhu, Wanru Xu, Weilin Yuan, Tingting Yang, Bing Jin, Yuwei Yan, Rui Chen, Siqi Wang, Jianhua Yao, Jiahong Xu, Zitong Wang, Guoping Li, Saumya Das, Liming Yang, Junjie Xiao · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104108 · 被引用次数：60 · 研究领域：Cardiac Fibrosis and Remodeling、MicroRNA in disease regulation、Congenital heart defects research

BACKGROUND: Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. METHODS: The expression level of miR-30d was analyzed in hypertrophy models and serum of patients with chronic heart failure by qRT-PCR. Gain and loss-of-function experiments of miR-30d were performed in vitro. miR-30d gain of function were performed in vivo. Bioinformatics, western blot, luciferase assay, qRT-PCR, and immunofluorescence were performed to examine the molecular mechanisms of miR-30d. FINDINGS: miR-30d was decreased in both murine and neonatal rat cardiomyocytes (NRCMs) models of hypertrophy. miR-30d overexpression ameliorated phenylephrine (PE) and angiotensin II (Ang II) induced hypertrophy in NRCMs, whereas the opposite phenotype was observed when miR-30d was downregulated. Consistently, the miR-30d transgenic rat was found to protect against isoproterenol (ISO)-induced pathological hypertrophy. Mechanistically, methyltransferase EZH2 could promote H3K27me3 methylation in the promotor region of miR-30d and suppress its expression during the pathological cardiac hypertrophy. miR-30d prevented pathological cardiac hypertrophy via negatively regulating its target genes MAP4K4 and GRP78 and inhibiting pro-hypertrophic nuclear factor of activated T cells (NFAT). Adeno-associated virus (AAV) serotype 9 mediated-miR-30d overexpression exhibited beneficial effects in murine ...