title: Atrial overexpression of angiotensin-converting enzyme 2 improves the canine rapid atrial pacing-induced structural and electrical remodeling. Fan, ACE2 improves atrial substrate remodeling.
abstract: The purpose of this study was to investigate whether atrial overexpression of angiotensin-converting enzyme 2 (ACE2) by homogeneous transmural atrial gene transfer can reverse atrial remodeling and its mechanisms in a canine atrial-pacing model. Twenty-eight mongrel dogs were randomly divided into four groups: Sham-operated, AF-control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP) and gene therapy with Ad-ACE2 (Ad-ACE2) (n = 7 per subgroup). AF was induced in all dogs except the Sham-operated group by rapid atrial pacing at 450 beats/min for 2 weeks. Ad-EGFP and Ad-ACE2 group then received epicardial gene painting. Three weeks after gene transfer, all animals except the Sham group underwent rapid atrial pacing for another 3 weeks and then invasive electrophysiological, histological and molecular studies. The Ad-ACE2 group showed an increased ACE2 and Angiotensin-(1-7) expression, and decreased Angiotensin II expression in comparison with Ad-EGFP and AF-control group. ACE2 overexpression attenuated rapid atrial pacing-induced increase in activated extracellular signal-regulated kinases and mitogen-activated protein kinases (MAPKs) levels, and decrease in MAPK phosphatase 1(MKP-1) level, resulting in attenuation of atrial fibrosis collagen protein markers and transforming growth factor-β1. Additionally, ACE2 overexpression also modulated the tachypacing-induced up-regulation of connexin 40, down-regulation of connexin 43 and Kv4.2, and significantly decreased the inducibility and duration of AF. ACE2 overexpression could shift the renin-angiotensin system balance towards the protective axis, attenuate cardiac fibrosis remodeling associated with up-regulation of MKP-1 and reduction of MAPKs activities, modulate tachypacing-induced ion channels and connexin remodeling, and subsequently reduce the inducibility and duration of AF.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
authors.forename: Jinqi
authors.initials: J
authors.lastname: Fan
authors.forename: Lili
authors.initials: L
authors.lastname: Zou
authors.forename: Kun
authors.initials: K
authors.lastname: Cui
authors.forename: Kamsang
authors.initials: K
authors.lastname: Woo
authors.forename: Huaan
authors.initials: H
authors.lastname: Du
authors.forename: Shaojie
authors.initials: S
authors.lastname: Chen
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Ling
authors.forename: Quanjun
authors.initials: Q
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Xianbin
authors.initials: X
authors.lastname: Lan
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zrenner
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Yin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics*; D064752:Atrial Remodeling; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D054638:Dual Specificity Phosphatase 1 / Q000502:physiology; D005260:Female; D015316:Genetic Therapy; D006325:Heart Atria / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D054638:Dual Specificity Phosphatase 1; D007703:Peptidyl-Dipeptidase A; D000085962:Angiotensin-Converting Enzyme 2