title: MicroRNA-365 accelerates cardiac hypertrophy by inhibiting autophagy via the modulation of Skp2 expression.
abstract: Evidence is emerging of a tight link between cardiomyocyte autophagy and cardiac hypertrophy (CH). Sustained exposure to stress leads CH to progress to heart failure. Several miRNAs have been described in heart failure, and miRNA-based therapeutic approaches are being pursued. Although microRNA-365 (miR-365) has been testified as a positive modulator of CH, the specific mechanism remains unclear. In the present study, we observed that miR-365 expression was up-regulated in hypertrophic cardiomyocytes both in vivo and in vitro, and was accompanied by dysregulation of autophagy. We found that miR-365 negatively modulates autophagy in hypertrophic cardiomyocytes by targeting Skp2. Overexpression of Skp2 promoted autophagy and rescued CH induced by Ang-II; conversely, Skp2 knockdown further inhibited autophagy and CH. Furthermore, we found that the activation of mammalian target of rapamycin (mTOR) signaling was regulated by Skp2 following Ang-II treatment, as indicated by the up-regulation of p-S6K and p-4EBP1 levels. The inactivation of mTOR by rapamycin completely abolished the Ang-II-induced inhibition of autophagy. In conclusion, our study provides substantial evidence that miR-365 and its target gene Skp2 play a functional role in CH and suggests the development of novel therapeutic options based on miR-365 and Skp2.
authors.affiliation: Department of Cardiology, The People's Hospital of Hebei Province, Shijiazhuang, Hebei 050000, China. Electronic address: haibowures@163.com.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Ultrasound, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
authors.forename: Yuncan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The People's Hospital of Hebei Province, Shijiazhuang, Hebei 050000, China.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The People's Hospital of Hebei Province, Shijiazhuang, Hebei 050000, China.
authors.forename: Ruyi
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Cardiology, The People's Hospital of Hebei Province, Shijiazhuang, Hebei 050000, China.
authors.forename: Deyun
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1 / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D032383:Myocytes, Cardiac / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000071186:Beclin-1; C000589043:MIRN365 microRNA, mouse; C480860:Map1lc3b protein, mouse; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D044786:S-Phase Kinase-Associated Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Autophagy; Cardiac hypertrophy; MicroRNA-365 (miR-365); Skp2; mTORC1 signaling