The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling
Abstract
Atrial structural remodelling including atrial hypertrophy and fibrosis is a key mediator of atrial fibrillation (AF). We previously demonstrated that the matricellular protein CCN5 elicits anti‐fibrotic and anti‐hypertrophic effects in left ventricles under pressure overload. We here determined the utility of CCN5 in ameliorating adverse atrial remodelling and arrhythmias in a murine model of angiotensin II (AngII) infusion. Advanced atrial structural remodelling was induced by AngII infusion in control mice and mice overexpressing CCN5 either through transgenesis (CCN5 Tg) or AAV9‐mediated gene transfer (AAV9‐CCN5). The mRNA levels of pro‐fibrotic and pro‐inflammatory genes were markedly up‐regulated by AngII infusion, which was significantly normalized by CCN5 overexpression. In vitro studies in isolated atrial fibroblasts demonstrated a marked reduction in AngII‐induced fibroblast trans‐differentiation in CCN5‐treated atria. Moreover, while AngII increased the expression of phosphorylated CaMKII and ryanodine receptor 2 levels in HL‐1 cells, these molecular features of AF were prevented by CCN5. Electrophysiological studies in ex vivo perfused hearts revealed a blunted susceptibility of the AAV9‐CCN5–treated hearts to rapid atrial pacing‐induced arrhythmias and concomitant reversal in AngII‐induced atrial action potential prolongation. These data demonstrate the utility of a gene transfer approach targeting CCN5 for reversal of adverse atrial structural and electrophysiological remodelling.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 04, 2020
- Source ID
- 10.1111/jcmm.15789
Entities
People
- Dongtak Jeong
- Eun‐kyoung Choi
- Hyun Kook
- Jimeen Yoo
- Min Ho Song
- Minah Lee
- Miyoung Lee
- Nour Raad
- Roger J. Hajjar
- Seung Pil Jang
- Tae Hwan Kwak
- Tae‐joon Cha
- Woo Jin Park
Organizations
- Chonnam National University
- Gwangju Institute of Science and Technology
- Hanyang University
- Icahn School of Medicine at Mount Sinai
- Kosin University
- National Research Foundation of Korea
- United States Department of Defense