MiR‐451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1

Journal of Cellular and Molecular Medicine

Lei Song²  Ming Su²  Shuiyun Wang³  Yubao Zou²  Xiaojian Wang²  Yilu Wang¹  Hongli Cui⁴  Peng Zhao⁴  Rutai Hui² 

[1] China Meitan General Hospital, Beijing, China;State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;Department of Pathology, Affiliated Hospital of Qingdao University Medical College, Qingdao, China

关键词: hypertrophic cardiomyopathy;    microRNA‐451;    tuberous sclerosis complex 1;    autophagy;    microRNAs microarray;   

DOI  :  10.1111/jcmm.12380

来源: Wiley

【 摘 要 】

Abstract

The molecular mechanisms that drive the development of cardiac hypertrophy in hypertrophic cardiomyopathy (HCM) remain elusive. Accumulated evidence suggests that microRNAs are essential regulators of cardiac remodelling. We have been suggested that microRNAs could play a role in the process of HCM. To uncover which microRNAs were changed in their expression, microRNA microarrays were performed on heart tissue from HCM patients (n = 7) and from healthy donors (n = 5). Among the 13 microRNAs that were differentially expressed in HCM, miR-451 was the most down-regulated. Ectopic overexpression of miR-451 in neonatal rat cardiomyocytes (NRCM) decreased the cell size, whereas knockdown of endogenous miR-451 increased the cell surface area. Luciferase reporter assay analyses demonstrated that tuberous sclerosis complex 1 (TSC1) was a direct target of miR-451. Overexpression of miR-451 in both HeLa cells and NRCM suppressed the expression of TSC1. Furthermore, TSC1 was significantly up-regulated in HCM myocardia, which correlated with the decreased levels of miR-451. As TSC1 is a known positive regulator of autophagy, we examined the role of miR-451 in the regulation of autophagy. Overexpression of miR-451 in vitro inhibited the formation of the autophagosome. Conversely, miR-451 knockdown accelerated autophagosome formation. Consistently, an increased number of autophagosomes was observed in HCM myocardia, accompanied by up-regulated autophagy markers, and the lipidated form of LC3 and Beclin-1. Taken together, our findings indicate that miR-451 regulates cardiac hypertrophy and cardiac autophagy by targeting TSC1. The down-regulation of miR-451 may contribute to the development of HCM and may be a potential therapeutic target for this disease.

【 授权许可】

CC BY   
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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