attribué à Jérôme MONTNAC'H

Reduction of Nav1.5 in cardiac fibroblasts may fine-tune cardiac remodeling and fibrosis in Scn5a+/- mice.

Jérôme Montnach, Mickaël Derangeon, Cynthia Ore Cerpa,
Isabelle Barò, Flavien Charpentier  
Inserm UMR_S915, CNRS ERL3147, l'institut du thorax, Nantes, France    

Loss-of-function mutations of SCN5A, the gene encoding the cardiac Na+ channel Nav1.5, are associated with progressive cardiac conduction defects and the Brugada syndrome, which both exhibit variable phenotypic penetrance. In order to understand Nav1.5 implication in these syndromes, a mouse model invalidated for Scn5a at the heterozygous state (Scn5a+/-) was developed. We previously observed that Scn5a+/- mice show variable degrees of ventricular conduction disorders and that Scn5a+/- mice with severe conduction defects (QRS>19 ms) develop extensive fibrosis during ageing Fibrosis is known to be due to accumulation of extracellular matrix and absence of degradation. Cardiac fibroblasts are known to be key players in this turn-over. We hypothesized that fibroblasts could express Nav1.5 channel and that reduced expression of Nav1.5 in Scn5a+/- mice could partly explain ageing-related development of fibrosis. Nav1.5 expression was investigated in cultured cardiac fibroblasts at 4, 6, 8 and 10 days after isolation from 10 weeks old mice. Our western blot results demonstrated that Nav1.5 channel is expressed in cardiac fibroblasts from wild-type mice and that this expression is reduced during fibroblasts differentiation in myofibroblasts. In cardiac fibroblasts isolated from Scn5a+/- mice we observed that reduction of Nav1.5 expression is in relation with a reduction of fibroblast differentiation. Cardiac fibroblasts are known to express and secrete different factors. When they differentiate into myofibroblasts their proteome and secretome is modified. In this context, we observed that -SMA (alpha-smooth muscle actin), Connexin 43, MMP9 (matrix metalloproteinase type 9), RhoA and Smad2 expression in cardiac fibroblasts isolated from 10 weeks old Scn5a+/- mice differs from that in wild-type fibroblasts. Secreted cytokines are currently investigated by BioPlex technique. In wild-type mice treated with flecainide (50 mg/kg per os daily), an inhibitor of cardiac sodium channel, we also observed a reduction of -SMA expression in total heart. To summarize, we can suppose that reduced expression of Nav1.5 sodium channel in cardiac fibroblasts could alter their differentiation and proliferation. These observations allow us to suppose that this difference of phenotype in cardiac fibroblasts could fine tune fibrosis development in Scn5a+/- mice.  

Key words : fibrosis, cardiac fibroblast, Nav1.5, Cx43, differentiation