title: MiR-451 is decreased in hypertrophic cardiomyopathy and regulates autophagy by targeting TSC1.
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.
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Ming
authors.initials: M
authors.lastname: Su
authors.forename: Shuiyun
authors.initials: S
authors.lastname: Wang
authors.forename: Yubao
authors.initials: Y
authors.lastname: Zou
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.forename: Yilu
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongli
authors.initials: H
authors.lastname: Cui
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Rutai
authors.initials: R
authors.lastname: Hui
authors.forename: Jizheng
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C531201:MIRN451 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C000624650:TSC1 protein, human; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins
keywords: autophagy; hypertrophic cardiomyopathy; microRNA-451; microRNAs microarray; tuberous sclerosis complex 1