セキネ　ヒデカズ   SEKINE Hidekazu   関根　秀一    所属   医学研究科 医学研究科 (医学部医学科をご参照ください)    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読なし
表題	SNRK regulates TGFβ levels in atria to control cardiac fibrosis
掲載誌名	正式名：bioRxiv
掲載区分	国外
巻・号・頁	pp.Preprint
国際共著	国際共著
著者・共著者	Karthikeyan Thirugnanam†, Farhan Rizvi, Arshad Jahangir, Peter Homar, Fathima Shabnam, Sean P. Palecek, Suresh N. Kumar, Amy Pan, Xiaowen Bai, SEKINE Hidekazu, Ramani Ramchandran*
発行年月	2024/09/26
概要	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 (TGFβ1) in the atrial cardiomyocytes. In HL-1 adult immortalized mouse atrial cells, using siRNA approaches, we show that Snrk knockdown cells show more TGFβ1 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 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.
DOI	10.1101/2024.09.24.612951
PMID	39386731