SEKINE Hidekazu    Department   Graduate School of Medical Science, Graduate School of Medical Science    Position   Associate Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	SNRK facilitates cardiac repair associated with nonischemic fibrosis: regulating transforming growth factor-beta1 levels in atrial cardiomyocytes
Journal	Formal name：Regenerative Medicine Reports ISSN code：3050-6794
Domestic / Foregin	Foregin
Publisher	Wolters Kluwer
Volume, Issue, Page	2(2),pp.45-52
International coauthorship	International coauthorship
Author and coauthor	Karthikeyan Thirugnanam†, Farhan Rizvi, Arshad Jahangir, Peter Homar, Fathima Shabnam, Sean P Palecek, Suresh N Kumar, Amy Pan, Xiaowen Bai, Hidekazu Sekine, Ramani Ramchandran*
Publication date	2025/06/01
Summary	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.
DOI	10.4103/REGENMED.REGENMED-D-25-00009
PMID	40584789