Inhibitory Effect Of Matrine On Isoproterenol-induced Myocardial Hypertrophy In Rats Via The Modulation Of Akt/mTOR/p70S6K Signaling Pathway And Its Molecular Mechanism

Objectives This study was aimed to observe whether the inhibitory effect of matrineon isoproterenol-induced rats myocardial hypertrophy in rats was associated with themodulation of Akt/mTOR/p70S6K signaling pathway, and to explain its molecularmechanism.Methods ISO (5mg·kg-1) were subcutaneously injected to male rats to establish themodel of chronic pathologic cardiac hypertrophy, the randomly divided into the normalcontrol group (the normal group), the matrine (50,100and200mg·kg-1, respectively)+ISOgroups (the matrine treatment groups), the ISO model group (the ISO group), the propranolol(10mg·kg-1)+ISO group (the propranolol group) and the matrine-alone (200mg·kg-1) group.24h after the seven-day drug administration, blood was collected from the right carotid artery,serum samples were separated and stored at-20°C for assay. The ratios of heart weight tobody weight (HW/BW) and left ventricular weight to body weight (LVW/BW) weredetermined, and heart morphometry was assessed. The cardiac apexes from each-group ratswere excised and fixed in10%neutral buffered formalin and the tissues were embedded inparaffin, sectioned and stained with hematoxylin and eosin (HE) to observe myocardialpathology. The enzyme-linked immunosorbent assay was performed for IGF-1and TGF-β1levels in the serum. Western blotting was utilized to detect p-Akt/Akt, mTOR/p-mTOR andp70S6K/p-p70S6K expression in the left ventricular tissues. Key findings Compared with the normal group, the ISO group rat’s body weight wassignificantly decreased, while the ratios of HW to BW and LVW to BW were markedlyincreased after the medication use. But there was no significant difference between thematrine-alone group and the normal group in those aspects. Matrine and propranololattenuated histopathological abnormalities of cardiomyocyte hypertrophy, myocardial fibrosis,interstitial edema and infiltration of inflammatory cells. In comparison with the normal group,serum IGF-1and TGF-β1levels in the ISO group were increased. Compared with the ISOgroup, the serum IGF-1and TGF-β1levels in the matrine treatment groups and propranololgroup fell dramatically. In contrast, those between the matrine-alone group and the normalgroup exhibited no significant difference. Western blot assays showed that compared with thenormal group, the expression of p-Akt (Ser473) and Akt was significantly reduced, whereasthat of p-mTOR, p-p70S6K and p70S6K was markedly increased, in the myocardial tissues inthe ISO group rats. Martrine and propranolol upregulated the expression of p-Akt (Ser473)and Akt in the myocardial tissues in rats. Simultaneously, they downregulated the expressionof p70S6K and phosphorylation of mTOR Ser2448and p70S6K Thr389. The levels of mTORhad no difference among all groups.Conclusions Matrine can inhibit isoptroterenol-induced rat myocardial hypertrophy inrats and its mechanism may be related to the activation p-Akt/Akt and inhibition ofmTOR/p70S6K signaling pathway.