Effect of icosapent ethyl on susceptibility to ventricular arrhythmias in postinfarcted rat hearts: Role of GPR120-mediated connexin43 phosphorylation.

Abstract

The ω-3 fatty acids exert as an antioxidant via the G protein-coupled receptor 120 (GPR120). Icosapent ethyl, a purified eicosapentaenoic acid, showed a marked reduction in sudden cardiac death. Connexin43 is sensitive to redox status. We assessed whether icosapent ethyl attenuates fatal arrhythmias after myocardial infarction, a status of high oxidative stress, through increased connexin43 expression and whether the GPR120 signalling is involved in the protection. Male Wistar rats after ligating coronary artery were assigned to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress. In concert, myocardial connexin43 levels revealed a significant decrease in vehicle-treated infarcted rats compared with sham. These changes of oxidative-nitrosative stress and connexin43 levels were blunted after icosapent ethyl administration. Provocative arrhythmias in the infarcted rats treated with icosapent ethyl were significantly improved than vehicle. Icosapent ethyl significantly increased GPR120 compared to vehicle after infarction. The effects of icosapent ethyl on superoxide and connexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative-nitrosative stress and connexin43 phosphorylation were abolished by administering AH-7614, an inhibitor of GPR120. SIN-1 abolished the Cx43 phosphorylation of icosapent ethyl without affecting GPR120 levels. Taken together, chronic use of icosapent ethyl after infarction is associated with up-regulation of connexin43 phosphorylation through a GPR120-dependent antioxidant pathway and thus plays a beneficial effect on arrhythmogenic response to programmed electrical stimulation.

• Authors: Wei-Ting Chen, Syue-Yi Chen, De-Wei Wu, Cheng-Che Lee, Tsung-Ming Lee
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 16 Pg. 9267-9279 (08 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32639107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Connexin 43
• Ffar4 protein, rat
• Gja1 protein, rat
• Lipid Regulating Agents
• Receptors, G-Protein-Coupled
• eicosapentaenoic acid ethyl ester
• Eicosapentaenoic Acid

Topics

• Animals
• Connexin 43 (genetics, metabolism)
• Eicosapentaenoic Acid (analogs & derivatives, pharmacology)
• Lipid Regulating Agents (pharmacology)
• Male
• Myocardial Infarction (complications)
• Phosphorylation
• Rats
• Rats, Wistar
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Tachycardia, Ventricular (drug therapy, etiology, metabolism, pathology)