Protective Effects Of Hexarelin On Ischemia/Reperfusion Cardiomyocytes And The Underlying Mechanisms

Myocardial ischemia/reperfusion(I/R)injury is the phenomenon that ischemic myocardial injury aggravates after restorement of oxygen and blood supply,mainly representing as:1)oxidative stress;2)calcium overload;3)aggravated inflammation;4)myocardium apoptosis;5)vascular endothelium dysfunction;6)no reflow;7)cardioelectric unstabilty.Hexarelin,a synthetic growth hormone-releasing peptide,is proved to possess cardioprotective actions in I/R of cardiomyocytes,myocardial infarction,myocardial fibrosis and atherosclerosis.Hexarelin carries out its cardiovascular effect through binding to the growth hormone secretagogue receptor(GHSR)1a and the non-GHSR receptor CD36.However,its effect on myocardial I/R injury in vivo has not been fully clarified and the underlying mechanisms are still unknown.We aimed to determine:1)whether hexarelin treatment could protect cardiomyocytes from I/R injury;2)whether the influence of hexarelin on I/R cardiomyocytes is related to IL-1 signaling pathway;3)whether the effect of hexarelin on IL-1 signaling pathway has connection with activation of the cardiac GHSR 1a receptor.In vivo hearts of male SD rats underwent 30 min ischemia by left coronary artery ligation and following reperfusion.Then the rats were treated with hexarelin,ghrelin or saline for 7 days.Echocardiography,malondialdehyde detection and histochemical stain were performed after treatment in order to evaluate the effect of hexarelin on myocardial I/R injury.In addition,immunohistochemisty,RT-PCR and Western blot were used to examine the expression level of IL-1 signaling pathway,and further we studied the function of GHSR la receptor in the above process by usage of GHSR la receptor antagonist.Our study showed that hexarelin treatment improved cardiac systolic function,decreased malondialdehyde production and increased the number of survival cardiomyocytes after myocardial I/R injury.The beneficial effects of hexarelin treatment were superior to those of equimolar ghrelin treatment.We meanwhile confirmed that hexarelin changed the expression of IL-1 signaling pathway in I/R myocardium,which could be partly neutralized by the GHSR 1a receptor antagonist.Based on the above findings,we conclude:1)hexarelin could effectively protect in vivo cardiomyocytes from I/R injury,manifesting in inhibition of oxygen radicals production,increase of survival myocardium and improvement of cardiac systolic function;2)the protective effects of hexarelin accomplish by modification of IL-1 signaling pathway;3)the influence of hexarelin on IL-1 signaling pathway is the consequence of activating cardiac GHSRla receptor.This article explains the protective effects of hexarelin on I/R cardiomyocytes and the underlying mechanisms,providing a new strategy to treatment of myocardial I/R injury.