Involvement of ER stress‐mediated sEH Activation in Myocardial Ischemia‐Reperfusion Injury

Abstract

ObjectivesPrevious studies have suggested the role of endoplasmic reticulum (ER) stress in myocardial ischemia/reperfusion (I/R) injury and inhibition of soluble epoxide hydrolase (sEH) was found to be protective against I/R‐induced injury. Whether ER stress mediates myocardial I/R injury via regulating sEH remains uninvestigated. The present study aimed to understand the role of ER stress‐sEH signaling in cardiac and coronary function in an in vitro rat model of myocardial I/R.MethodsIsolated rat hearts were randomly divided into four groups including control, I/R, and I/R groups pretreated with either the IRE1α inhibitor GSK2850163 or the sEH inhibitor dicyclohexylurea (DCU). The hearts were mounted on a Langendorff apparatus and I/R groups were subjected to 30‐min global ischemia followed by 60‐min reperfusion. GSK2850163 and DCU were perfused for 15 min prior to the onset of ischemia. Left ventricular function was monitored during the experiment. Branches of the left anterior descending artery were isolated after I/R for study of endothelium‐dependent vasorelaxation in a myograph. The protein expression of IRE1, phosphorylated IRE1 (p‐IRE1), and sEH was determined by western blotting.ResultsLeft ventricular end diastolic pressure (LVEDP) was increased and the maximum velocity of contraction (+dp/dtmax) and relaxation (‐dp/dtmax) of the left ventricle was decreased during I/R, which could be partially reversed by GSK2850163 or DCU pretreatment. Relaxant response of coronary artery to acetylcholine was also improved by GSK2850163 or DCU. Inhibition of IRE1 phosphorylation by GSK2850163 significantly downregulated the protein expression of sEH.ConclusionsActivation of sEH induced by the IRE1 branch of ER stress is involved in I/R‐induced cardiac dysfunction, in which impairment of coronary dilator function is an important contributing factor.Support or Funding InformationSupported by NSFC 81870227 & 81870288, Tianjin Science and Technology Commission (18PTZWHZ00060) & Binhai New Area Health Bureau (2018BWKZ005), and Non‐profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2018TX31002 & 2019XK310001.