Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis

Chao-Shun Chan; Fong-Jhih Lin; Yao-Chang Chen; Yung-Kuo Lin; Satoshi Higa; Shih-Ann Chen; Yi-Jen Chen

doi:10.3390/ijms241713100

Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis

Int J Mol Sci. 2023 Aug 23;24(17):13100. doi: 10.3390/ijms241713100.

Authors

Chao-Shun Chan^{1

2}, Fong-Jhih Lin^{3

4}, Yao-Chang Chen⁴, Yung-Kuo Lin^{1

5}, Satoshi Higa⁶, Shih-Ann Chen^{7

8

9}, Yi-Jen Chen^{5

10

11}

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
² Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan.
³ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan.
⁵ Division of Cardiology, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
⁶ Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 9012131, Japan.
⁷ Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
⁸ Institute of Clinical Medicine and Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan.
⁹ Cardiovascular Center, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
¹⁰ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
¹¹ Cardiovascular Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca²⁺ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca²⁺ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca²⁺/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na⁺/Ca²⁺ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca²⁺ current, NCX current, and late Na⁺ current in PV cardiomyocytes without altering Na⁺ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca²⁺ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca²⁺ homeostasis, thereby reducing PV arrhythmogenesis.

Keywords: atrial fibrillation; glucagon-like peptide-1 receptor agonist; pulmonary vein.

MeSH terms

Amides
Animals
Anti-Arrhythmia Agents
Atrial Fibrillation*
Bone Density Conservation Agents*
Calcium
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Cyclic AMP-Dependent Protein Kinases
Glucagon-Like Peptide 1 / pharmacology
Glucagon-Like Peptide-1 Receptor
Homeostasis
Hormone Antagonists
Pulmonary Veins*
Rabbits

Substances

N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
Glucagon-Like Peptide-1 Receptor
2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
Calcium
KN 93
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Hormone Antagonists
Anti-Arrhythmia Agents
Amides
Bone Density Conservation Agents
Cyclic AMP-Dependent Protein Kinases
Glucagon-Like Peptide 1

Grants and funding

This research was made possible with the support of the National Science and Technology Council of Taiwan, under grant numbers NSTC 110-2314-B-038-126-MY2 and NSTC 112-2314-B-038-102-. Additionally, the study also received funding from Taipei Medical University Hospital, as part of the project 111TMUH-MOST-22, and Foundation for the Development of Internal Medicine in Okinawa, Japan (4-02-004, 4-02-005). We are grateful for the financial backing provided by these institutions, which contributed to the successful completion of this work.