Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2

Desheng Li; Yang Liu; Changzhu Li; Zhiwen Zhou; Kangyi Gao; Hairong Ba; Jiming Yang; Genlong Xue; Dechun Yin; Xinbo Zhao; Kewei Shen; Lingmin Zhang; Jialiang Li; Chenhong Li; Jiahui Song; Lexin Zhao; Yao Pei; Lina Xuan; Yang Zhang; Yanjie Lu; Zhi-Ren Zhang; Baofeng Yang; Yue Li; Zhenwei Pan

doi:10.1161/CIRCULATIONAHA.123.067517

Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2

Circulation. 2024 May 10. doi: 10.1161/CIRCULATIONAHA.123.067517. Online ahead of print.

Authors

Desheng Li^#¹, Yang Liu^#², Changzhu Li^#¹, Zhiwen Zhou^#¹, Kangyi Gao¹, Hairong Ba¹, Jiming Yang¹, Genlong Xue³, Dechun Yin², Xinbo Zhao², Kewei Shen¹, Lingmin Zhang¹, Jialiang Li¹, Chenhong Li¹, Jiahui Song¹, Lexin Zhao¹, Yao Pei¹, Lina Xuan¹, Yang Zhang¹, Yanjie Lu¹, Zhi-Ren Zhang^{2

4}, Baofeng Yang¹, Yue Li^{2

4}, Zhenwei Pan^{1

2

4

5}

Affiliations

¹ National Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education, International Cooperation Base for Major Cardiovascular Diseases in Cold Regions, China), College of Pharmacy (D.L., Changzhu Li, Z.Z., K.G., H.B., J.Y., K.S., L. Zhang, J.L., Chenhong Li, J.S., L. Zhao, Y.P., L.X., Y.Z., Y. Lu, B.Y., Z.P.).
² National Key Laboratory of Frigid Zone Cardiovascular Diseases, Department of Cardiology (Y. Liu, D.Y., X.Z., Z.-R.Z., Y. Li, Z.P.).
³ Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, China (G.X.).
⁴ NHC Key Laboratory of Cell Transplantation (Z.-R.Z., Y. Li, Z.P.).
⁵ First Affiliated Hospital, Harbin Medical University, China. Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019 Research Unit 070, Harbin, China (Z.P.).

^# Contributed equally.

PMID: 38726666
DOI: 10.1161/CIRCULATIONAHA.123.067517

Abstract

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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ overload. The phosphorylation level of CREB (cyclic AMP responsive element binding protein 1) was upregulated in atrial tissues of SPX-KO and GALR2-cKO mice. Chromatin immunoprecipitation confirmed the recruitment of p-CREB to the proximal promoter regions of KCNJ2 and SLN. Finally, spexin treatment suppressed CREB signaling, decreased I_K1 current and intracellular Ca²⁺ overload, which thus reduced the inducibility of AF in Ang-II-infused mice.

Conclusions: Spexin reduces atrial fibrillation susceptibility by inhibiting CREB phosphorylation and thus downregulating KCNJ2 and SLN transcription by GALR2 receptor. The spexin/GALR2/CREB signaling pathway represents a novel therapeutic avenue in the development of agents against atrial fibrillation.

Keywords: CREB; IK1; SLN; atrial fibrillation; galanin receptors; spexin.