miR-452-5p mediates SCN5A dependent fibrosis via TGF-beta/SMAD4 axis

SCN5A coding for sodium channels in the heart and its reduced activity implicated various biological processes including fibrogenesis. However, the mechanistic interplay between loss of SCN5A activity and cardiac fibrosis pertinence remains elusive. In-vitro knockdown of the SCN5A gene activates fibroblasts and increases TGF-β signaling with small-RNA sequencing indicating its impact on miR-452-5P expression in human cardiac fibroblasts (HCF). Mechanistically, miR-452-5p acts as a direct regulator of TGF-β signaling by inhibiting SMAD4 expression, maintaining cellular homeostasis in normal physiological conditions. SCN5A knockdown limits miR-452-5p regulatory function on SMAD4, which further promotes cardiac fibrosis (CF). These results clarify the significant involvement of miR-452-5p in CF development and propose a promising target for potential therapeutic intervention. To investigate the role of SCN5A in CF, we established SCN5A-knockdown cell model by shRNA. We then performed a small RNA-seq to analyze the microRNA expression profiles affected by SCN5A knockdown in human cardiac fibroblasts.