Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis
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 Ca<sup>2+</sup> homeostasis, which is crucial in pulmonary vein (PV,...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13100 |
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| author | Chao-Shun Chan Fong-Jhih Lin Yao-Chang Chen Yung-Kuo Lin Satoshi Higa Shih-Ann Chen Yi-Jen Chen |
| author_facet | Chao-Shun Chan Fong-Jhih Lin Yao-Chang Chen Yung-Kuo Lin Satoshi Higa Shih-Ann Chen Yi-Jen Chen |
| author_sort | Chao-Shun Chan |
| collection | DOAJ |
| description | 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup>/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na<sup>+</sup>/Ca<sup>2+</sup> 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 Ca<sup>2+</sup> current, NCX current, and late Na<sup>+</sup> current in PV cardiomyocytes without altering Na<sup>+</sup> current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca<sup>2+</sup> 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 Ca<sup>2+</sup> homeostasis, thereby reducing PV arrhythmogenesis. |
| first_indexed | 2024-03-10T23:22:12Z |
| format | Article |
| id | doaj.art-04979443ccc84522b539be8040f19f38 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:22:12Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-04979443ccc84522b539be8040f19f382023-11-19T08:12:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124171310010.3390/ijms241713100Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium HomeostasisChao-Shun Chan0Fong-Jhih Lin1Yao-Chang Chen2Yung-Kuo Lin3Satoshi Higa4Shih-Ann Chen5Yi-Jen Chen6Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Biomedical Engineering, National Defense Medical Center, Taipei 11490, TaiwanDivision of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanCardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 9012131, JapanHeart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, TaiwanDivision of Cardiology, Department of Internal Medicine, Wan-Fang Hospital, Taipei Medical University, Taipei 11696, TaiwanGlucagon-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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup>/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na<sup>+</sup>/Ca<sup>2+</sup> 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 Ca<sup>2+</sup> current, NCX current, and late Na<sup>+</sup> current in PV cardiomyocytes without altering Na<sup>+</sup> current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca<sup>2+</sup> 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 Ca<sup>2+</sup> homeostasis, thereby reducing PV arrhythmogenesis.https://www.mdpi.com/1422-0067/24/17/13100glucagon-like peptide-1 receptor agonistatrial fibrillationpulmonary vein |
| spellingShingle | Chao-Shun Chan Fong-Jhih Lin Yao-Chang Chen Yung-Kuo Lin Satoshi Higa Shih-Ann Chen Yi-Jen Chen Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis International Journal of Molecular Sciences glucagon-like peptide-1 receptor agonist atrial fibrillation pulmonary vein |
| title | Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis |
| title_full | Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis |
| title_fullStr | Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis |
| title_full_unstemmed | Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis |
| title_short | Glucagon-like Peptide-1 Receptor Activation Reduces Pulmonary Vein Arrhythmogenesis and Regulates Calcium Homeostasis |
| title_sort | glucagon like peptide 1 receptor activation reduces pulmonary vein arrhythmogenesis and regulates calcium homeostasis |
| topic | glucagon-like peptide-1 receptor agonist atrial fibrillation pulmonary vein |
| url | https://www.mdpi.com/1422-0067/24/17/13100 |
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