MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation

Dongjiu Li,1,* Chengyu Mao,1,* En Zhou,1,* Jiayin You,2,* Erhe Gao,3 Zhihua Han,1 Yuqi Fan,1 Qing He,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 2Depa...

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Autores principales:	Li D, Mao C, Zhou E, You J, Gao E, Han Z, Fan Y, He Q, Wang C
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	cardiac fibrosis myocardial infarction microrna-21 sprouty1 erk/tgf-β/smad signaling pathway Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ffd65b152fb5408481c70cab87847ed1
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spelling	oai:doaj.org-article:ffd65b152fb5408481c70cab87847ed12021-12-02T13:02:37ZMicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation1178-7031https://doaj.org/article/ffd65b152fb5408481c70cab87847ed12020-11-01T00:00:00Zhttps://www.dovepress.com/microrna-21-mediates-a-positive-feedback-on-angiotensin-ii-induced-myo-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Dongjiu Li,1,* Chengyu Mao,1,* En Zhou,1,* Jiayin You,2,* Erhe Gao,3 Zhihua Han,1 Yuqi Fan,1 Qing He,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 2Department of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 3Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA*These authors contributed equally to this workCorrespondence: Changqian Wang Email wangcqdr17@163.comObjective: Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis.Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function.Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang II-induced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1.Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/TGF-β/Smad pathway. Therefore, targeting the miR-21–Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.Keywords: cardiac fibrosis, myocardial infarction, microRNA-21, Sprouty1, ERK/TGF-β/Smad signaling pathwayLi DMao CZhou EYou JGao EHan ZFan YHe QWang CDove Medical Pressarticlecardiac fibrosismyocardial infarctionmicrorna-21sprouty1erk/tgf-β/smad signaling pathwayPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 13, Pp 1007-1020 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	cardiac fibrosis myocardial infarction microrna-21 sprouty1 erk/tgf-β/smad signaling pathway Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	cardiac fibrosis myocardial infarction microrna-21 sprouty1 erk/tgf-β/smad signaling pathway Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Li D Mao C Zhou E You J Gao E Han Z Fan Y He Q Wang C MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation
description	Dongjiu Li,1,* Chengyu Mao,1,* En Zhou,1,* Jiayin You,2,* Erhe Gao,3 Zhihua Han,1 Yuqi Fan,1 Qing He,1 Changqian Wang1 1Department of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 2Department of Emergency, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, People’s Republic of China; 3Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA*These authors contributed equally to this workCorrespondence: Changqian Wang Email wangcqdr17@163.comObjective: Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis.Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function.Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang II-induced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1.Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/TGF-β/Smad pathway. Therefore, targeting the miR-21–Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.Keywords: cardiac fibrosis, myocardial infarction, microRNA-21, Sprouty1, ERK/TGF-β/Smad signaling pathway
format	article
author	Li D Mao C Zhou E You J Gao E Han Z Fan Y He Q Wang C
author_facet	Li D Mao C Zhou E You J Gao E Han Z Fan Y He Q Wang C
author_sort	Li D
title	MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation
title_short	MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation
title_full	MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation
title_fullStr	MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation
title_full_unstemmed	MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation
title_sort	microrna-21 mediates a positive feedback on angiotensin ii-induced myofibroblast transformation
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/ffd65b152fb5408481c70cab87847ed1
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MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation

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