Article Dans Une Revue Pharmacological Research Année : 2020

Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a− mice

Claire Castro
  • Fonction : Auteur
Isabelle Baró
Flavien Charpentier
Mickaël Derangeon

Résumé

Na.LS Gap junction GW788388 Cardiac fibroblasts Down-regulation of Connexin43 (Cx43) has often been associated with the development of cardiac fibrosis. We showed previously that ScnSa heterozygous knockout mice (ScnS a+ 1-¡, which mimic familial progressive cardiac conduction defect, exhibit an age-dependent decrease of Cx43 expression and phosphorylation concomitantly with activation of TGF-¡3 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 ScnSa + t-mice. We observed in 60-week-old ScnSa+I-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-¡3 canonical pathway activation. ln conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in ScnSa+I-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.

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hal-03086843 , version 1 (23-12-2020)

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Justine Patin, Claire Castro, Marja Steenman, Agnès Hivonnait, Agnès Carcouët, et al.. Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a− mice. Pharmacological Research, 2020, 159, pp.104922. ⟨10.1016/j.phrs.2020.104922⟩. ⟨hal-03086843⟩
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