期刊
PHARMACOLOGICAL RESEARCH
卷 159, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2020.104922
关键词
Danegaptide; ZP 1609; Na(v)1.5; Gap junction; GW788388; Cardiac fibroblasts
资金
- European Community's Seventh Framework Programme FP7/2007-2013 [HEALTH-F2-2009-241526]
- EUTrigTreat
- Agence Nationale de la Recherche [ANR-12-BSV1-0013-01]
- Federation Francaise de Cardiologie (FFC)
- DHU2020
- Fondation Genavie
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV1-0013] Funding Source: Agence Nationale de la Recherche (ANR)
Down-regulation of Connexin43 (Cx43) has often been associated with the development of cardiac fibrosis. We showed previously that Scn5a heterozygous knockout mice (Scn5a(+)(/-)), which mimic familial progressive cardiac conduction defect, exhibit an age-dependent decrease of Cx43 expression and phosphorylation concomitantly with activation of TGF-beta pathway and fibrosis development in the myocardium between 45 and 60 weeks of age. The aim of this study was to investigate whether Gap-134 prevents Cx43 down-regulation with age and fibrosis development in Scn5a(+)(/-) mice. We observed in 60-week-old Scn5a(+)(/-) mouse heart a Cx43 expression and localization remodeling correlated with fibrosis. Chronic administration of a potent and selective gap junction modifier, Gap-134 (danegaptide), between 45 and 60 weeks, increased Cx43 expression and phosphorylation on serine 368 and prevented Cx43 delocalization. Furthermore, we found that Gap-134 prevented fibrosis despite the persistence of the conduction defects and the TGF-beta canonical pathway activation. In conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in Scn5a(+)(/-) mice. Finally, our study suggests that gap junction modifier, such as Gap-134, could be an effective anti-fibrotic agent in the context of age-dependent fibrosis in progressive cardiac conduction disease.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据