Effect And Mechanism Of Mineralocorticoid Receptor Antagonist In Ventricular Remodeling In Early Spontaneously Hypertensive Rats

Objective:To investigate the effect and mechanism of mineralocorticoid receptor antagonist Eplerenone in the early stage of ventricular remodeling in spontaneously hypertensive rats(SHR).Methods:12-week-old male spontaneously hypertensive rats(SHR)were randomly divided into : SHR-Veh group,SHR-EPL30 group(30 mg/(kg·d)of epridone),SHR-EPL100group(100 mg/(kg·d)of epridone),Wistar Kyoto(WKY)rats as control group.Each rat in the SHR-EPL 30 and SHR-EPL100 group was weighed and measured as eplerenone according to their body weight.The SHR-Veh and WKY groups received 2ml of sterile water.Sercontinuous gavage for 8 weeks.The cardiac mass index and echocardiographic parameters of rats were measured.The morphological changes of myocardial tissue of rats were observed by HE staining.The expression of mineralocorticoid receptor in rat heart was measured by immunohistochemistry.The protein expressions of Beclin-1,LC3,P62,AMPK and m TOR were detected by immunohistochemistry and Western blot.Results:Compared with WKY group,the heart mass index of SHR-Veh group was higher(P<0.001).Echocardiographic results after 8 weeks of administration:Compared with SHR-Veh group,the IVSd and LVPWd of SHR-EPL30 and SHR-EPL100 group rats were lower than those of SHR-Veh group after administration(P<0.05).The results of HE:Compared with SHR-Veh group,Eprinone obviously reduced the cross-sectional area of myocardial cells in SHR-EPL30 group(P<0.05).Immunohistochemical results:The expression of MR In myocardial tissue of SHR-Veh group was higher than that of WKY group(P<0.001).Eplerenone reduced the expression of Mineralocorticoid receptor(MR)in myocardial tissue of SHR-EPL30 group(P<0.05);Compared with WKY group,the expression of autophagic proteins Beclin-1 and LC3 B in myocardial tissue of SHR-Veh group increased evidently(P<0.001);Compared with SHR-Veh group,the expression of Beclin-1 and LC3 B protein was decreased in SHR-EPL30 group(P<0.05),and the expression level of P62 in myocardial tissue of SHR-EPL30 group was markedly increased(P<0.05);In SHR-EPL30 group,the expression level of AMPK increased in myocardial tissue(P<0.05),while the expression of m TOR protein showed decreased(P<0.05).Western blot results:Compared with SHR-Veh group,the expression level of Beclin-1 protein in heart tissue of SHR-EPL30 and SHR-EPL100 group decreased(P<0.05),The ratio of LC3B-II/LC3B-I in SHR-EPL30 group(P<0.01)and SHR-EPL100group(P<0.05)decreased,and the expression level of P62 protein increased in SHR-EPL30 and SHR-EPL100 group(P<0.001),The expression level of AMPK protein in myocardial tissue of SHR-EPL30 group and SHR-EPL100 group increased(P<0.05),while the expression level of m TOR protein in myocardial tissue of SHR-EPL30 group decreased(P<0.05).Conclusion:Eplerenone can improve early ventricular remodeling in SHR rats by inhibiting autophagy of cardiomyocytes.Low-dose eplerenone exerts cardioprotective effect independent of hypotension.Eplerenone ameliorates early ventricular remodeling in SHR rats by affecting AMPK,m TOR protein expression.Regulating autophagy is not through AMPK / m TOR signaling pathway,but other mechanisms may regulate autophagy in the heart of SHR rats.