KCNE2 Attenuates Myocardial Injury In Diabetic Cardiomyopathy By Inhibiting Endoplasmic Reticulum Stress And Apoptosis

AIM:KCNE2 expression was decreased in diabetic cardiomyopathy,and cardiac function was impaired in mice with KCNE2 gene knockout,however the mechanisms underlying the development of diabetic cardiomyopathy relating to KCNE2 deficiency remain unclear.This study aims to explore the role and mechanism of KCNE2 in the regulation of diabetic cardiomyopathy and investigate the possible therapeutic effect of manipulating KCNE2 expression in the treatment of diabetic cardiomyopathy.METHODS:This experiment established models of diabetic cardiomyopathy both in neonatal rats cardiomyocytes(NRCMs)with palmitic acid sodium(PA,0.4mM)stimulation and in mice through high-fat diet combined with small doses of STZ injection.Endoplasmic reticulum(ER)stress was determined by examining the proteins levels of ER stress proteins,HSPA5 and CHOP,and apoptosis was determined by the protein levels of apoptotic protein cleaved-caspase3 and TUNEL assay.KCNE2 expression in NRCMs and in mouse hearts were manipulated by transfecting the cells with KCNE2-carrying adenovirus and injecting AAVKCNE2 through mouse tail veins.RESULTS:(1)The expressions of KCNE2 protein were decreased in PA-stimulated NRCMs in a dose-dependent manner from 0.1-0.4 mM,and in heart tissues from mice with type II diabetic cardiomyopathy,as well as db/db knockout mice.(2)PA stimulation(0.4mM)induced endoplasmic reticulum stress(ER stress),where the protein levels of HSPA5 and CHOP were significantly increased.Furthermore,PA induced apoptosis indicated by the increase in the expression of apoptotic protein cleaved caspase-3,as well as TUNEL staining(P < 0.01).(3)MAPK cascades,including ERK、JNK and p38,which involve in ER stressinduced apoptosis were activated in PA-stimulated cells.(4)Overexpression of KCNE2 suppressed the ER stress and apoptosis in NRCMs upon PA stimulation.Meanwhile,KCNE2 overexpression-largely inhibited the activation of MAPK pathway.(5)The cardiac function in high-fat fed mice was impaired,indicated by the-increased left ventricular end-systolic diameter(LVIDs)and end-diastolic diameter(LVIDd),decreased ejection fraction(EF)and shortened fraction(FS).Injection of AAV-KCNE2 improved cardiac function in high fat dietinduced cardiomyopathy,where the LVIDs was decreased,and EF and FS were increased.(6)ER stress and apoptosis were increased in heart tissues from high-fat fed mice,and AAVKCNE2 treatment reduce the ER stress and apoptosis.CONCLUSION:(1)The expression of KCNE2 is down-regulated in PA-stimulated NRCMs and in mice with diabetic cardiomyopathy.(2)ER stress and apoptosis are induced both in PA-stimulated NRCMs and in high-fat diet-induced cardiomyopathy;MAPK pathways are activated by PA stimulation and high-fat diet,mediating ER stress-induced apoptosis.(3)KCNE2 overexpression suppressed PA-induced ER stress and apoptosis,and the activation of MAPK pathways;(4)Increasing KCNE2 expression in heart improves cardiac function by inhibiteding ER stress and apoptosis in high-fat diet-induced diabetic cardiomyopathy in mice.