The matricellular protein CCN5 prevents adverse atrial structural and electrical remodellingopen access
- Authors
- Lee, Min-Ah; Raad, Nour; Song, Min Ho; Yoo, Jimeen; Lee, Miyoung; Jang, Seung Pil; Kwak, Tae Hwan; Kook, Hyun; Choi, Eun-Kyoung; Cha, Tae-Joon; Hajjar, Roger J.; Jeong, Dongtak; Park, Woo Jin
- Issue Date
- Oct-2020
- Publisher
- WILEY
- Keywords
- atrial fibrillation; atrial fibrosis; CaMKII; CCN5
- Citation
- JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, v.24, no.20, pp.11768 - 11778
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
- Volume
- 24
- Number
- 20
- Start Page
- 11768
- End Page
- 11778
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/834
- DOI
- 10.1111/jcmm.15789
- ISSN
- 1582-1838
- 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.
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