SNRK facilitates cardiac repair associated with nonischemic fibrosis: Regulating transforming growth factor-beta1 levels in atrial cardiomyocytes
Recommended Citation
Thirugnanam K, Rizvi F, Jahangir A, et al. SNRK facilitates cardiac repair associated with nonischemic fibrosis: regulating transforming growth factor-beta1 levels in atrial cardiomyocytes. Regenerative Medicine Reports. 2025;2(2):45-52. doi:10.4103/regenmed.Regenmed-d-25-00009
Abstract
Heart failure is a pressing clinical condition that is expected to increase as our population ages and thus requires better treatment options. Identifying the precise mechanisms that underlie fibrosis and inflammation, two key features associated with cardiac repair and regeneration during ischemic and nonischemic heart failure, is likely to provide effective strategies for the clinical intervention of heart failure. This study investigated a metabolic serine threonine kinase gene, sucrose nonfermenting-related kinase (SNRK), which we previously reported to control cardiac metabolism and function. Conditional knockout of Snrk in mouse cardiomyocytes (Snrk cmcKO) leads to deleterious fibrosis, inflammation, and, subsequently, heart failure. The precise mechanism underlying cardiomyocyte SNRK-driven repression of deleterious cardiac fibrosis in nonischemic heart failure-mediated cardiac repair and regeneration is not known. Here, using mouse, rat, and human tissues, we demonstrated that SNRK expression is increased in the atrial chamber, especially in left atrial cardiomyocytes. Using a nonischemic heart failure mouse model, we showed that fibrosis in the atria, particularly the left atria, is associated with cardiac functional decline. To elucidate the mechanistic pathway responsible for the SNRK-mediated repression of cardiac fibrosis, we focused on the profibrotic protein transforming growth factor-β1. Transforming growth factor-β1 levels in Snrk siRNA-knockdown HL-1 adult immortalized mouse atrial cells were higher compared with control siRNA-knockdown HL-1 cells. Coculture of HL-1 cardiomyocytes (-/+Snrk) with cardiac fibroblasts in vitro revealed that SNRK represses transforming growth factor-β1 signaling (Smad2/3) in cardiac fibroblasts and cardiac fibroblast activation (alpha-smooth muscle actin marker). We conclude that under nonischemic heart failure conditions, increased SNRK expression in the atria is associated with a cardioprotective mechanism by controlling the release of the profibrotic transforming growth factor-β1 factor. These studies illuminate a potential deleterious fibrosis pathway for intervention during cardiac repair and regeneration in nonischemic heart failure.
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