Loss-of-function mutations in SCN5A, the gene encoding Nav1.5 channel, have been associated with inherited progressive cardiac conduction disease (PCCD). We have proposed that Scn5a heterozygous knock-out (Scn5a+/-) mice, which are characterized by ventricular fibrotic remodeling with ageing, represent a model for PCCD. Our objectives were to identify the molecular pathway involved in fibrosis development and prevent its activation. Methods and results: Our study shows that myocardial interstitial fibrosis occurred in Scn5a+/- mice only after 45 weeks of age. Fibrosis was triggered by TGF-β pathway activation. Younger Scn5a+/- mice were characterized by a higher connexin 43 expression than wildtype (WT) mice. After the age of 45 weeks, connexin 43 expression decreased in both WT and Scn5a+/- mice, although the decrease was larger in Scn5a+/- mice. Chronic inhibition of cardiac sodium current with flecainide (50 mg/kg/day p.o) in WT mice from the age of 6 weeks to the age of 60 weeks did not lead to TGF-β pathway activation and fibrosis. Chronic inhibition of TGF-β receptors with GW788388 (5 mg/kg/day p.o.) in Scn5a+/- mice from the age of 45 weeks to the age of 60 weeks prevented the occurrence of fibrosis. However, current data could not detect reduction in QRS duration with GW788388. Conclusion: Myocardial fibrosis secondary to a loss of Nav1.5 is triggered by TGF-β signaling pathway. Those events are more likely secondary to the decreased Nav1.5 sarcolemmal expression rather than the decreased Na+ current per se. TGF-β receptor inhibition prevents age-dependent development of ventricular fibrosis in Scn5a+/- mouse.
TGF-β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease
Mickael Derangeon, Jérôme Montnach, Cynthia Ore Cerpa, Benoit Jagu, Justine Patin, Gilles Toumaniantz, Aurore Girardeau, Christopher LH Huang, William H. Colledge, Andrew A Grace, Isabelle Baró, Flavien Charpentier; TGF-β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease. Cardiovasc Res 2017 cvx026. doi: 10.1093/cvr/cvx026
Download citation file:
© 2017 Oxford University Press×