Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2

作者：Desheng Li, Yang Liu, Changzhu Li, Changzhu Li, Zhiwen Zhou, Kangyi Gao, Hairong Bao, Jiming Yang, Genlong Xue, Dechun Yin, Xinbo Zhao, Kewei Shen, Lingmin Zhang, Jialiang Li, Chenhong Li, Chenhong Li, Jiahui Song, Lexin Zhao, Yao Pei, Lina Xuan, Yang Zhang, Yanjie Lu, Zhi‐Ren Zhang, Baofeng Yang, Yue Li, Zhenwei Pan · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.123.067517 · 被引用次数：24 · 研究领域：Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology、Signaling Pathways in Disease

BACKGROUND: G protein–coupled receptors play a critical role in atrial fibrillation (AF). Spexin is a novel ligand of galanin receptors (GALRs). In this study, we investigated the regulation of spexin and GALRs on AF and the underlying mechanisms. METHODS: Global spexin knockout (SPX-KO) and cardiomyocyte-specific GALRs knockout (GALR-cKO) mice underwent burst pacing electrical stimulation. Optical mapping was used to determine atrial conduction velocity and action potential duration. Atrial myocyte action potential duration and inward rectifying K + current ( I K1 ) were recorded using whole-cell patch clamps. Isolated cardiomyocytes were stained with Fluo-3/AM dye, and intracellular Ca 2+ handling was examined by CCD camera. A mouse model of AF was established by Ang-II (angiotensin II) infusion. RESULTS: Spexin plasma levels in patients with AF were lower than those in subjects without AF, and knockout of spexin increased AF susceptibility in mice. In the atrium of SPX-KO mice, potassium inwardly rectifying channel subfamily J member 2 ( KCNJ2 ) and sarcolipin ( SLN ) were upregulated; meanwhile, I K1 current was increased and Ca 2+ handling was impaired in isolated atrial myocytes of SPX-KO mice. GALR2-cKO mice, but not GALR1-cKO and GALR3-cKO mice, had a higher incidence of AF, which was associated with higher I K1 current and intracellular Ca 2+ overload. The phosphorylation level of CREB (cyclic AMP responsive element binding protein 1) was upregulated in atrial tissue...