SNRK regulates TGFbeta levels in atria to control cardiac fibrosis

Thirugnanam, K.; Rizvi, F.; Jahangir, A.; Homar, P.; Shabnam, F.; Palecek, S. P.; Kumar, S. N.; Pan, A.; Bai, X.; Sekine, H.; Ramchandran, R.

doi:10.1101/2024.09.24.612951

bioRxiv · 10.1101/2024.09.24.612951

SNRK regulates TGFbeta levels in atria to control cardiac fibrosis

Thirugnanam, K.·Rizvi, F.·Jahangir, A.·Homar, P.·Shabnam, F.·Palecek, S. P.·Kumar, S. N.·Pan, A.·Bai, X.·Sekine, H.·Ramchandran, R.

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Abstract

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, sucrose non-fermenting related kinase (SNRK), that we previously reported to control cardiac metabolism and function. Conditional knockout of Snrk in mouse cardiomyocytes (Snrk 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 (TGF{beta}1) in the atrial cardiomyocytes. In HL-1 adult immortalized mouse atrial cells, using siRNA approaches, we show that Snrk knockdown cells show more TGF{beta}1 secretion, which was also observed in heart lysates from Snrk cardiac-specific knockout mice in vivo. These effects were exacerbated upon infusion of Angiotensin II. Results from Snrk knockdown cardiomyocytes co-cultured with cardiac fibroblasts suggest that SNRK represses TGF{beta}1 signaling (Smad 2/3) in atrial CMs and prevents paracrine cardiac fibroblast activation (-SMA marker). In conclusion, high SNRK expression in atria regulates cardiac homeostasis, by preventing the release of TGF{beta}1 secretion to block cardiac fibrosis. These studies will assist in developing heart chamber-specific fibrosis therapy for non-ischemic HF and AF.

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Thirugnanam, K., Rizvi, F., Jahangir, A., Homar, P., Shabnam, F., Palecek, S. P., Kumar, S. N., Pan, A., Bai, X., Sekine, H., Ramchandran, R.. 2024-09-26. SNRK regulates TGFbeta levels in atria to control cardiac fibrosis. https://doi.org/10.1101/2024.09.24.612951

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