Icarrin Attenuates Left Ventricle Remodeling Induced By Isoproterenol Via Down-regulating The Endoplasmic Reticulum Stress And Mitochondrial Apoptotic Pathway

Objective: To study the protective effect of icariin(ICA)on the left ventricle remodeling in mice induced by isoproterenol(ISO),and to explore whether its underlying mechanism is related to the regulation of ERS and mitochondrial apoptosis pathway.Methods: Fifty male mice of seven weeks were randomly divided into the control group,ISO group,ISO + ICA 15 mg/kg group,ISO + ICA 60 mg/kg group,and ISO + losartan group.The 5 mg/kg/d of ISO was subcutaneously injected to induce the left ventricle remodeling model.The control group was injected with the equal volume of saline.And mice in the two ICA groups were intragastrically administered ICA of 15 mg/kg/d and 60mg/kg/d,respectively.Furthermore,mice in the losartan group were intragastrically administered losartan of 9 mg/kg/d.At the same time,the ISO and control groups were intragastrically administered the equal volume of double-distilled water.After 14 days of treatment,left ventricular function was measured,and the heart mass index(HMI)and left ventricular mass index(LVMI)were calculated.H&E staining was used to observe the pathological changes of mice in the left ventricle.TUNEL staining was used to monitor the cardiomyocyte apoptosis in the left ventricle.Western blotting was used to detect the protein levels of GRP78,ATF6,ATF4,CHOP,DR5,p53,Bax,Bcl-2,Cyt C,Cleaved-Caspase9 and Cleaved-Caspase3,and the phosphorylation levels of PERK,ASK1,JNK,p38 and Bad.Results: Compared to the control group,LVIDs and LVIDd were obviously increased(P<0.05),and LVAWs,LVAWd,LVPWs,LVPWd,EF and FS were significantly decreased(P<0.05);The LVMI and HMI were increased(P<0.05);H&E staining exhibited that disorder of cardiomyocyte arrangement,the cardiac myocytes swelled,and partial myocardial cells and TDM showed that the myocardial space in the left ventricle was widened;the results of TUNEL staining showed that the number of positive myocardial were increased(P<0.05);Western blotting demonstrated that the protein levels of GRP78,ATF6,ATF4,CHOP,DR5,p53,Bax,Cyt C,Cleaved-caspase9 and Cleaved-caspase3 were increased(P<0.05),and the protein level of Bcl-2 was decreased(P<0.05),and the ratio of Bax/Bcl-2 was increased(P<0.05),and the phosphorylation levels of PERK,ASK1,JNK,p38 and Bad were increased significantly(P<0.05)in the ISO group.However,compared to the ISO group,LVIDs and LVIDd were decreased obviously(P<0.05);LVAWs,LVAWd,LVPWs,LVPWd,EF and FS were increased significantly(P<0.05);The LVMI and HMI were decreased(P<0.05);Pathological deformity was improved in the left ventricle;The myocardial apoptosis of left ventricle was decreased(P<0.05);Western blotting indicated that the protein levels of GRP78,ATF6,ATF4,CHOP,DR5,p53,Bax,Cyt C,Cleaved-Caspase9 and Cleaved-Caspase3 were decreased(P<0.05),and the protein level of Bcl-2 was increased(P<0.05),and the ratio of Bax/Bcl-2 was decreased(P<0.05),and the phosphorylation levels of PERK,ASK1,JNK,p38 and Bad were decreased significantly(P<0.05)in the ICA(60mg/kg)and losartan groups.Meanwhile,ICA(60mg/kg)and losartan groups have no obviously difference.Conclusion: Icariin attenuates the left ventricle remodeling in mice induced by ISO,and the mechanism was related to down-regulating of the ERS and mitochondrial apoptotic pathway.