Preventive Effects Of Matrine On Ventricular Remodeling Of Chronic Heart Failure Rats And Its Molecular Mechanism

Objectives This study was designed to explore the preventive effect of matrine, an active component of Chinese traditional medicine, on cardiac remodeling and heart dysfunction in isoproterenol-induced chronic heart failure rats.Methods Heart failure was established in Sprague-Dawley rats by daily subcutaneous injection of isoproterenol (ISO, 5mg/kg/d) for seven days. Simutaneously, the rat body weights, myocardial hypertrophy indexes, myocardial injury biomarkers, histopathological examination as well as hemodynamic parameters were observed to evaluate effect of matrine on cardiac remodeling and heart dysfunction in isoproterenol-induced heart failure rats. In addition, cardiac myocyte diameter(CD) and cross section area(CSA)as well as interstitial collagen content were also measured.Key findings The rat body weights had no significant differences among all groups (all P>0.05). Compared with the control, myocardial hypertrophy indexes and myocardial injury biomarker were increased, showing the rats in ISO group had significant myocardial hypertrophy with cell necrosis or apoptosis. Histopathological examination demonstrated that CD and CSA as well as interstitial collagen content were significantly increased. Besides, the heart function of rats in ISO group was decreased, as shown by decreased left ventricular systolic pressure (LVSP) and maximal rate of increase of left ventricular pressure (LV dP/dt_max) and increased left ventricular end diastolic pressure (LVEDP) and maximal rate of decrease of left ventricular pressure (LV dP/dt_min)(P<0.01), demonstrating the rats had been progression to heart failure. Meanwhile, systolic arterial pressure(SAP) and heart rate(HR) were significantly decreased (P<0.05), However, diastolic blood pressure(DBP) showed no changes between groups. Oral administration of matrine (25, 50 or 100 mg/kg per day for 7 days respectively) significantly reduced the increased myocardial hypertrophy indexes and the levels of LDH, CK as well as cTn-I elevated in plasma in ISO-induced heart failure rats, also improved the dysfunction of left ventricular (LV) shown by the increased LVSP and LV dP/dt_max and the decreased LVEDP and LV dP/dt_min. Histopathological examination demonstrated that matrine could reduce the increased CD and CSA of cardiac myocyte and the interstitial collagen content, inhibiting cardiac myocyte hypertrophy and interstitial fibrosis in the isoproterenol-induced heart failure rats.Conclusions Our results suggest that matrine has a significant preventive effect on cardiac remodeling and heart dysfunction in isoproterenol-induced heart failure in Sprague-Dawley rats.Objective To explore the possible drug targets under various signal pathways such as PI3Kγ/Akt/GSK-3β, PRMT1/DDAH2/NOS/NO, ODC/SSAT in matrine in prevention of cardiac remodeling in isoproterenol-induced heart failure in Sprague-Dawley rats. Methods The serum levels of NO and ADMA were respectively detected by ELISA method and biochemistry method, and the protein content of PI3Kγ, Akt, p-Akt(Ser473), p-Akt(Thr308), GSK-3, p-GSK-3β(Ser9), iNOS, eNOS, p-eNOS(Ser1177), PRMT1, DDAH2, ODC, SSAT in myocardial tissue were measured by the method of Western blot.Key findings Compared with the control, the serum level of NO in isoproterenol group was decreased, but ADMA increased, and the protein levels of PI3Kγ, Akt, p-Akt(Ser473), p-Akt(Thr308), p-GSK-3β(Ser9), iNOS, PRMT1, ODC and SSAT were significantly increased while the contents of GSK-3β, eNOS, p-eNOS(Ser1177) and DDAH2 were markedly decreased. Matrine(25,50 and 100mg/kg) treatment could significantly reverse the up-regulation of PI3Kγ, Akt, p-Akt(Ser473), p-Akt(Thr308), p-GSK-3β(Ser9), iNOS and ODC and down-regulation of GSK-3β, eNOS, p-eNOS(Ser1177) and DDAH2 in isoproterenol group; However, it has no effect on the elevated PRMT1 and SSAT in isoproterenol group.Conclusion The effect of matrine against cardiac remodeling was attributed to modulation of PI3Kγ/Akt/GSK-3βpathway, up-regulation of eNOS and DDAH2 followed by the enhanced metabolism of ADMA (an endogenous competitive inhibitor of eNOS), and the level of nitric oxide restored. In addition, it is associated with down-regulation of ODC protein expression in heart tissues of heart failure rats, which results in decreased polyamines production.