Correlation Between Receptors For Advanced Glycation End Products And Myocardial Ischemia-reperfusion Injury

BACKGROUND: Currently,the main clinical treatment for myocardial infarction is percutaneous transluminal coronary angioplasty or coronary artery bypass grafting,thrombolysis to achieve timely restoration of blood perfusion of the ischemic myocardium,however,after myocardial ischemia and reperfusion,reperfusion arrhythmias can occur,myocardial dystrophy,metabolic abnormalities and changes in myocardial ultrastructure,which has been termed myocardial ischemia-reperfusion injury,how to reduce and avoid myocardial ischemia-reperfusion injury has become one of the most important research contents of reperfusion therapy.RAGE is a member of the immunoglobulin superfamily and participates in a variety of pathophysiological processes including lesions of target organs of diabetes,atherosclerosis,and diseases of the tumor,nervous system,etc,when associated with its ligands AGEs,HMGB1,s100/calcium granule protein and other combinations promote disease development.Our previous experimental results are consistent with most of the literature reports.The expression of RAGE and HMGB1 increases when ischemia-reperfusion injury occurs,but it has not been confirmed whether blocking RAGE can avoid or reduce the occurrence of myocardial ischemia-reperfusion injury.In addition,animal experiments and clinical studies in recent years have found that transient ischemic reperfusion of organs and tissues distant from the heart can also produce a similar cardioprotective effect called remote ischemic preconditioning/postconditioning.Regardless of cell experiments,animal models or clinical trials,the myocardial protective effects of remote ischemic postconditioning have been well documented.This intervention is time-predictable and relatively simple to use,it is more suitable for clinical treatment than ischemic preconditioning,but whether the protection of remote ischemic postconditioning is achieved through the regulation of RAGE is rarely reported.Our group mainly investigated whether Advanced Glycation End Product Receptors play role in Remote ischemia postconditioning attenuating myocardial ischemia-reperfusion injury and related signaling pathway conduction.OBJECTIVE: To investigate the role of RAGE in ischemia-reperfusion injury and to verify whether RAGE is involved in remote ischemic postconditioning.METHODS:(1)Healthy male C57BL/6J mice of 7-9 weeks old were selected as experimental subjects.Myocardial ischemia-reperfusion injury model was established by ligation of the left anterior descending coronary artery in mice and randomly divided into sham operation group,FPS-ZM1(RAGE blocker)control group,ischemia reperfusion group,FPS-ZM1+ischemia-reperfusion group.One week after operation,the hemodynamic parameters were measured with a small animal heart beater.The ultrastructure of the myocardium was observed by HE staining.The RAGE ligands HMGB1,P-AKT/AKT,and P-ERK/ ERK protein expression level were detected by Western blotting.(2)Healthy 7-9-week-old male C57BL/6J mice were randomly divided into sham group,ischemia-reperfusion,group,remote ischemic postconditioning group,FPS-ZM1+ischemia-reperfusion group,and FPS-ZM1+remote ischemic postconditioning.Mice were subjected to hyperthermia,HE staining,and Western blotting to investigate the effect of two interventions,ie,remote ischemic postconditioning and blocking RAGE,on myocardial ischemia-reperfusion injury.RESULTS: Compared with ischemia-reperfusion group,the FPS-ZM1+ ischemiareperfusion group had improved cardiac function index EF% and FS%,myocardial injury was milder,RAGE ligand HMGB1 protein decreased,P-AKT/AKT and P-ERK /ERK protein expression levels increased;The EF% and FS% in the remote ischemic postconditioning group has no significance in those in the ischemiareperfusion group,but the degree of surgical injury to the myocardium was significantly reduced,and the expression of HMGB1 was significantly reduced,P-AKT/AKT and P-ERK/ERK protein expression levels increased.Compared with remote ischemic postconditioning group and FPS-ZM1+ ischemia-reperfusion group,respectively,the FPS-ZM1+ remote ischemic postconditioning group did not futher increase the EF% and FS% of the cardiac function.However,the degree of myocardial injury in this group was significantly less than that in either group,and the expression of HMGB1 was further decreased and the expression levels of AKT/AKT and P-ERK/ERK were further increased.CONCLUSIONS: Both tagerting RAGE and tagerting RAGE+remote ischemic postconditioning can improve cardiac systolic function,but the combination of the two does not act synergistically;remote ischemic postconditioning and tagerting RAGE can reduce myocardial injury degree,the protective effect of RISK signal activation by blocking HMGB1-RAGE.In addition,the increase in RAGE blockers on the basis of remote ischemic postconditioning is more pronounced.