Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation

Wei Cao,&ast; Shuai Song,&ast; Guojian Fang,&ast; Yingze Li, Yuepeng Wang, Qun-Shan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this...

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Autores principales:	Cao W, Song S, Fang G, Li Y, Wang Y, Wang QS
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	atrial fibrillation atrial fibrosis atrial fibroblast cadherin-11 angiotensin-ii. Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ba983d5933394a848d03a0a19fc73ed8
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spelling	oai:doaj.org-article:ba983d5933394a848d03a0a19fc73ed82021-12-02T16:32:15ZCadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation1178-7031https://doaj.org/article/ba983d5933394a848d03a0a19fc73ed82021-07-01T00:00:00Zhttps://www.dovepress.com/cadherin-11-deficiency-attenuates-ang-ii-induced-atrial-fibrosis-and-s-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Wei Cao,&ast; Shuai Song,&ast; Guojian Fang,&ast; Yingze Li, Yuepeng Wang, Qun-Shan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qun-Shan Wang; Yuepeng Wang Email wangqunshan@xinhuamed.com.cn; wangyuepeng@xinhuamed.com.cnBackground: Atrial fibrosis serves as a disease initiating mechanism in the development of atrial fibrillation. Angiotensin II (Ang-II), a key mediator for atrial fibrosis, aberrantly activates atrial fibroblasts (AFs) into myofibroblasts, resulting in subsequent excessive synthesis and deposition of extracellular matrix (ECM). Cadherin-11 (CDH11) is essential in the development of non-cardiac fibrotic diseases. In this study, we investigated its role in the pathogenesis and underlying mechanism of atrial fibrillation.Methods: We obtained left atrial tissues from either patients with atrial fibrillation or Ang-II-induced atrial fibrosis mice. We utilized a global CDH11 knockout mouse (CDH11−/-) model to determine the effect of CDH11 on AF cell proliferation, migration, ECM synthesis/deposition. RNA-Seq of isolated AFs from CDH11−/- or normal mice was performed and differential expressed genes were analyzed. The mouse susceptibility to atrial fibrillation was examined by cardiac electrophysiology.Results: We found that cadherin-11 was significantly up-regulated in fibrotic atrial tissue from patients with atrial fibrillation and Ang-II-induced mice. Both normal and CDH11−/- mice did not develop atrial fibrosis at resting state. However, after Ang-II infusion, unlike severe atrial fibrosis occurred in normal mice, CDH11−/- mice displayed a reduced atrial fibrosis. Atrial fibroblasts with CDH11 deletion from CDH11−/- mice showed reduction in Ang-II-induced cell proliferation, migration and ECM synthesis/deposition, indicating the involvement of CDH11 in atrial fibrosis. Consistently, RNA-Seq of CDH11-null AFs uncovered significant decrease in pro-fibrotic gene expression. In addition, we identified reduction of transcripts associated with Smad2/3, ERK1/2 and JNK pathways. Further, CDH11−/- mice showed a significantly attenuated Ang-II-induced susceptibility to atrial fibrillation.Conclusion: Our results indicate that CDH11 potentiates Ang-II-induced activation of AFs. The pathogenesis of atrial fibrosis is through CDH11 mediated stimulation of Smad2/3, ERK1/2 and JNK pathways. Thus, CDH11 might serve as a novel therapeutic target for ameliorating the development of atrial fibrillation.Keywords: atrial fibrillation, atrial fibrosis, atrial fibroblast, cadherin-11, angiotensin-IICao WSong SFang GLi YWang YWang QSDove Medical Pressarticleatrial fibrillationatrial fibrosisatrial fibroblastcadherin-11angiotensin-ii.PathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 2897-2911 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	atrial fibrillation atrial fibrosis atrial fibroblast cadherin-11 angiotensin-ii. Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	atrial fibrillation atrial fibrosis atrial fibroblast cadherin-11 angiotensin-ii. Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Cao W Song S Fang G Li Y Wang Y Wang QS Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
description	Wei Cao,&ast; Shuai Song,&ast; Guojian Fang,&ast; Yingze Li, Yuepeng Wang, Qun-Shan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qun-Shan Wang; Yuepeng Wang Email wangqunshan@xinhuamed.com.cn; wangyuepeng@xinhuamed.com.cnBackground: Atrial fibrosis serves as a disease initiating mechanism in the development of atrial fibrillation. Angiotensin II (Ang-II), a key mediator for atrial fibrosis, aberrantly activates atrial fibroblasts (AFs) into myofibroblasts, resulting in subsequent excessive synthesis and deposition of extracellular matrix (ECM). Cadherin-11 (CDH11) is essential in the development of non-cardiac fibrotic diseases. In this study, we investigated its role in the pathogenesis and underlying mechanism of atrial fibrillation.Methods: We obtained left atrial tissues from either patients with atrial fibrillation or Ang-II-induced atrial fibrosis mice. We utilized a global CDH11 knockout mouse (CDH11−/-) model to determine the effect of CDH11 on AF cell proliferation, migration, ECM synthesis/deposition. RNA-Seq of isolated AFs from CDH11−/- or normal mice was performed and differential expressed genes were analyzed. The mouse susceptibility to atrial fibrillation was examined by cardiac electrophysiology.Results: We found that cadherin-11 was significantly up-regulated in fibrotic atrial tissue from patients with atrial fibrillation and Ang-II-induced mice. Both normal and CDH11−/- mice did not develop atrial fibrosis at resting state. However, after Ang-II infusion, unlike severe atrial fibrosis occurred in normal mice, CDH11−/- mice displayed a reduced atrial fibrosis. Atrial fibroblasts with CDH11 deletion from CDH11−/- mice showed reduction in Ang-II-induced cell proliferation, migration and ECM synthesis/deposition, indicating the involvement of CDH11 in atrial fibrosis. Consistently, RNA-Seq of CDH11-null AFs uncovered significant decrease in pro-fibrotic gene expression. In addition, we identified reduction of transcripts associated with Smad2/3, ERK1/2 and JNK pathways. Further, CDH11−/- mice showed a significantly attenuated Ang-II-induced susceptibility to atrial fibrillation.Conclusion: Our results indicate that CDH11 potentiates Ang-II-induced activation of AFs. The pathogenesis of atrial fibrosis is through CDH11 mediated stimulation of Smad2/3, ERK1/2 and JNK pathways. Thus, CDH11 might serve as a novel therapeutic target for ameliorating the development of atrial fibrillation.Keywords: atrial fibrillation, atrial fibrosis, atrial fibroblast, cadherin-11, angiotensin-II
format	article
author	Cao W Song S Fang G Li Y Wang Y Wang QS
author_facet	Cao W Song S Fang G Li Y Wang Y Wang QS
author_sort	Cao W
title	Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
title_short	Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
title_full	Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
title_fullStr	Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
title_full_unstemmed	Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation
title_sort	cadherin-11 deficiency attenuates ang-ii-induced atrial fibrosis and susceptibility to atrial fibrillation
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/ba983d5933394a848d03a0a19fc73ed8
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Cadherin-11 Deficiency Attenuates Ang-II-Induced Atrial Fibrosis and Susceptibility to Atrial Fibrillation

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