TGF-β1-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging.

摘要: Background— Mutations in the cardiac Na+ channel gene ( SCN5A ) can adversely affect electric function heart, but effects be age dependent. We explored interacting of Scn5a disruption and aging on pathogenesis sinus node dysfunction a heterozygous knockout +/−) mouse model. Methods Results— compared functional, histological, molecular features young (3 to 4 month) old (1 year) wild type +/− mice. Both were associated with decreased heart rate variability, reduced sinoatrial automaticity, slowed conduction. They also led increased collagen fibroblast levels upregulated transforming growth factor-β1 (TGF-β1) vimentin transcripts, providing measures fibrosis Nav1.5 expression. All these most noticeable inhibition by Nav1.5-E3 antibody directly TGF-β1 production both cultured human myocytes fibroblasts. Finally, was downregulation wide range ion related transcripts and, again, greatest The quantitative results from studies permitted computer simulations that successfully replicated observed phenotypes shown different experimental groups. Conclusions— These implicate tissue degeneration triggered deficiency manifesting as TGF-β1-mediated accompanied remodeling or aging. latter interact produce severe phenotype In demonstrating this, our findings suggest novel regulatory role for cellular biological processes addition its electrophysiologic function.