SNRK regulates TGFβ levels in atria to control cardiac fibrosis.

Atrial fibrosis is central to the pathology of heart failure (HF) and atrial fibrillation (AF). Identifying precise mechanisms underlying atrial fibrosis will provide effective strategies for clinical intervention. This study investigates a metabolic serine threonine kinase gene, that we previously reported to control cardiac metabolism and function. Conditional knockout of in mouse cardiomyocytes ( cmcKO) leads to atrial fibrosis and subsequently HF. The precise mechanism underlying cardiomyocyte SNRK-driven repression of fibrosis is not known. Here, using mouse, rat, and human tissues, we demonstrate that SNRK expression is high in atria, especially in atrial cardiomyocytes. SNRK expression correlates with lower levels of pro-fibrotic protein transforming growth factor-beta 1 (TGFβ1) in the atrial cardiomyocytes. In HL-1 adult immortalized mouse atrial cells, using siRNA approaches, we show that knockdown cells show more TGFβ1 secretion, which was also observed in heart lysates from cardiac-specific knockout mice in vivo. These effects were exacerbated upon infusion of Angiotensin II. Results from knockdown cardiomyocytes co-cultured with cardiac fibroblasts suggest that SNRK represses TGFβ1 signaling (Smad 2/3) in atrial CMs and prevents paracrine cardiac fibroblast activation (α-SMA marker). In conclusion, high SNRK expression in atria regulates cardiac homeostasis, by preventing the release of TGFβ1 secretion to block cardiac fibrosis. These studies will assist in developing heart chamber-specific fibrosis therapy for non-ischemic HF and AF.