Trimetazidine Protect Cardiomyopathy Via Inhibiting Endoplasmic Reticulum Stress

Heart failure is a common chronic cardiovascular disease in the world.According to the latest guideline of European Society of Cardiology(ESC),heart failure is defined as a clinical syndrome characterized of representative symptoms,such as breathlessness and ankle swelling,which always accompanies with structural and/or functional cardiac damage,arousing a decrease in cardiac output and/or an elevation in intracardiac pressures.It is not an independent disease,but the end stage of all cardiovascular diseases.Because of the high prevalence,morbidity,mortality and incidence rates,heart failure becomes a worldwide health problem.The therapies of heart failure indeed ameliorate the symptoms,however,they do not restrain the progression.It is urgent to explore new molecular mechanisms to provide more targetable and specific therapy for this disease,which is crucial to the development of new effective therapies.The endoplasmic reticulum is an organelle which plays an important role in cellular homeostasis,such as protein folding,calcium homeostasis maintaining and lipid biosynthesis.There are many factors that may injure the function of endoplasmic reticulum,including hypoxia,oxidative stress,ischemia,calcium overload,and overexpression of normal and/or misfolded proteins.All of the factors above may trigger the adaptive unfolded protein response(UPR)or endoplasmic reticulum stress(ERS).The ERS in certain extent is a cellular protective process.However,when the ERS is prolonged or excessive,the apoptosis pathway are initiated from the ER,leading to apoptotic cell death finally.Intracellular calcium has a vital impact on regulating cell contractility,gene expression,energy balance and apoptosis in the cardiac.It is essential to maintain a calcium homeostasis to preserve the normal function of myocardial cell.Sarcoplasmic reticulum calcium-transporting ATPase isoform 2a(SERCA2a)plays an important role in calcium transportation,and its activity will also influence the cardiac function.Trimetazidine(TMZ;1-(2,3,4-trimethhoxibenzyl)-piperazine dihydrochloride)is a famous drug for antianginal,shown beneficial effects on ischemic myocardial disease.Numerous experimental and clinical studies clarified that TMZ can shift the metabolic strategy thereby decrease the consumption of oxygen,remit the calcium-overload and protect the myocardial cell.However,the mechanisms of TMZ in cytoprotective effects during heart failure remain largely unknown.This study explored the protective effect the mechanisms of TMZ against ISO-induced heart failure.Methods and results:Firstly,the male C57 mice aged 8 weeks were randomly divided into 6 groups,each group with 8 mice.Before the sacrifice of the mice,the cardiac function was measured by Millar pressure volume systems and the ultrasonic cardiogram.The consequences exhibited that,compared with the sham group,the systolic and the diastolic function were decreased when the mice were treated with ISO.However,TMZ could improve the cardiac function damaged by ISO.Conversely,when the mice were given r AAV-si SERCA2 a,the beneficial effect of TMZ could be significantly inhibited.Secondly,the heart tissue and H9C2 cell were used to detect the rate of apoptosis.According to the results of TUNEL assay,we found that,ISO could induce the apoptosis of myocardial cell,and TMZ could obviously decrease the apoptosis.In contrary,the effects of TMZ could be reversed by r AAV-si SERCA2 a.The similar results was observed in the H9C2 cell lines.Finally,we performed western-blot assay with heart tissue and H9C2 cell to examine the expression of GRP78,CHOP and SERCA2 a.The results showed that ISO could improve the level of GRP78 and CHOP,while reduce the expression of SERCA2 a.The effect of ISO could be reversed by TMZ.However,when the si-SERCA2 a was used,TMZ would not exhibit these effects.Conclusion:Our study clarified that TMZ attenuated ISO-induced myocardial dysfunction.The cytoprotective effect of TMZ is exhibited through increasing the SERCA2 a expression,remitting the calcium-overload and inhibiting the apoptosis induced by ERS.These findings may provide a targetable therapeutic strategy for heart failure.