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Merck
CN

Targeting miR-30d reverses pathological cardiac hypertrophy.

EBioMedicine (2022-06-26)
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
摘要

Pathological cardiac hypertrophy occurs in response to numerous stimuli and precedes heart failure (HF). Therapies that ameliorate pathological cardiac hypertrophy are highly needed. 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. 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 hypertrophic model. Notably, miR-30d was reduced in serum of patients with chronic heart failure and miR-30d overexpression could significantly ameliorate pathological hypertrophy in human embryonic stem cell-derived cardiomyocytes. Overexpression of miR-30d may be a potential approach to treat pathological cardiac hypertrophy. This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J Xiao), National Natural Science Foundation of China (82020108002 to J Xiao, 81900359 to J Li), the grant from Science and Technology Commission of Shanghai Municipality (20DZ2255400 and 21XD1421300 to J Xiao, 22010500200 to J Li), Shanghai Sailing Program (19YF1416400 to J Li), the "Dawn" Program of Shanghai Education Commission (19SG34 to J Xiao), the "Chen Guang" project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation (19CG45 to J Li).

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Sigma-Aldrich
单克隆 抗-α-肌动蛋白(肌小节) 小鼠抗, clone EA-53, ascites fluid
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AC16 人心肌细胞细胞系, AC16 Human Cardiomyocytes can be serially passaged and can differentiate when cultured in mitogen-free medium. The cells may be used to study developmental regulation of cardiomyocytes.
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来自 普通小麦 的凝集素(小麦), FITC conjugate, lyophilized powder
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Anti-Rabbit IgG (Fc specific) antibody produced in goat, affinity isolated antibody, buffered aqueous solution