GPR120‐mediated Connexin43 Phosphorylation is Implicated in Antiarrhythmic Effects of Icosapent Ethyl in Post‐infarcted Rat Hearts

Abstract

AimsThe w‐3 fatty acids exert as an antioxidant via the G protein‐coupled receptor 120 (GPR120). Icosapent ethyl, a highly purified ethyl ester of 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 connnexin43 expression and whether the GPR120 signaling is involved in the protection.Methods and resultsMale Wistar rats after ligating coronary artery were randomized to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative‐nitrosative stress, as measured by myocardial superoxide, nitrotyrosine, and dihydroethidium fluorescent staining. In concert, myocardial connnexin43 levels revealed a significant decrease in vehicle‐treated infarcted rats compared with sham. These changes of oxidative‐nitrosative stress and connnexin43 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 connnexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative‐nitrosative stress and connnexin43 phosphorylation were abolished by administering AH‐7614, an inhibitor of GPR120. SIN‐1 abolished the Cx43 phosphorylation of IPE without affecting GPR120 levels.ConclusionsChronic use of icosapent ethyl after infarction is associated with up‐regulation of connnexin43 phosphorylation through a GPR120‐dependent antioxidant pathway and thus plays a role in the beneficial effect on arrhythmogenic response to programmed electrical stimulation.Support or Funding InformationThis work was supported by the grants of China Medical University (DMR‐108‐035) and Ministry of Science and Technology (MOST‐108‐2622‐B‐039‐002‐CC3), Taiwan.