The Effect And Underlying Mechanism Of Berberine On Improving Pressure Overload-induced Cardiac Hypertrophy And Dysfunction

Background:Cardiac hypertrophy is a maladaptive change in response to pressure overload, and is also one of potential risksfor developing heart failure.Autophagy,a highly conserved cytoprotective pathway,contributes to the quality control of proteins and organelles within cardiomyocytes under stress conditions.Upregulation of autophagy in pressure-overload induced hypertrophic hearts is an adaptive response for protecting myocytes from hemodynamic stess. Chinese traditional medcine berberine exerts the effcts of cardiacprotection and autophagy enhancement, but it is still unclear whether berberine’s cardioprotection is corelated with the autophgy enhacement.Object:In this study, we sought to determine whether enhanced autophagy could contribute to the cardioprotection of berberine in arat model of transverse aortic constriction (TAC)-induced cardiac hypertrophy and dysfunction, and to further delineate the underlying molecular mechanisms and signaling pathways by which berberine would exert its effects.Methods:There were four experimental groups: sham + vehicle group, TAC + vehicle group, TAC + berberine group, andTAC + berberine + 3-methyladenine (3-MA) group.Berberine (10 mg/kg/day, oral gavage administration) and 3-MA (100 mg/kg on alternate days, intraperitoneal injection)were administered immediately after the completion of TAC surgery for 4 weeks.Cardiac function was evaluated by echocardiography.H&Estaining, Masson’s trichrome staining, andTUNEL stainingwere carried out to test cardiomyocyte cross-sectional areas,the degree of fibrosis, and apoptosis respectively.The ultrastructure of cardiac myocytes and autophagosomes were examined by transmission electron microscopy assay.Autophagy associated protien and underlying signaling pathways were detected by western blotting and histopathological analyses.Results: In the current study, we observed that TACoperation induced a marked increase in heart size,the ratio of heart weight to body weight, cardiomyocyte apoptosis, myocardial fibrosis, and hypertrophic marker brain natriuretic peptide, all of which were effectively suppressed by berberine administration. In addition, berberineenhanced autophagy inhypertrophic hearts, which was accompanied by a decrease in heart size, cardiac apoptosis, and the attenuation of cardiac dysfunction.Furthermore, use of autophagyinhibitor 3-MA blocked berberine-induced autophagy level, and abrogated the protection of berberine againstheart hypertrophy, cardiac dysfunction, and apoptosis. Berberine ameliorated TAC-induced endoplasmic reticulum stress, which was alsoabolished by 3-MA. Moreover, berberine significantly inhibited the upstream signaling of autophagy, such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK1/2), and p38 mitogen-activated protein kinase (MAPK) phosphorylation.Conculsion:We conclude that berberine could attenuate left ventricular remodeling and cardiomyocyte apoptosis through an autophagy-dependent mechanism in a rat model of cardiac hypertrophy, which is, at least in part, associated with enhanced autophagy through inhibition of mTOR, p38 and ERK1/2 MAPK signaling pathways.