Effect And Mechanism Of Ginsenoside Rc In Alleviating Myocardial Ischemia Injury

Background: Myocardial ischemia is a leading cause of death and disability worldwide.Myocardial ischemia is caused by an imbalance between supply and demand of oxygen to the myocardium.Oxidative stress plays an important role in myocardial ischemia-induced cardiomyocyte damage.Myocardial ischemia also leads to the activation of leukocytes and recruitment of neutrophils,with the subsequent production of cytokines exacerbating the process of injury.Ginseng is a famous traditional Chinese medicine.Ginsenosides are the main active ingredients of ginseng.Ginsenosides have properties including antioxidant,anti-inflammatory,anti-apoptotic effects.Objective: To investigate the effect and mechanism of ginsenoside Rc on reducing myocardial injury induced by isoproterenol.Methods: Experiment 1 Male Swiss mice were randomly divided into 4 groups: control group,ginsenoside Rc 10,20,40 mg/kg groups.The mice in ginsenoside Rc groups were administrated intragastrically with ginsenoside Rc,while the mice in control group were administrated with the same volume of sodium carboxymethyl cellulose,once a day for 3 days.The pathological changes of myocardial tissue and the contents of CK-MB and troponin T in serum were evaluated.Experiment 2 Myocardial ischemia was induced by isoproterenol.Male Swiss mice were randomly divided into 5 groups: control group,model group,ginsenoside Rc 10,20,40 mg/kg groups.Mice in model group and ginsenoside Rc 10,20,40 mg/kg groups were injected subcutaneously with isoproterenol at a dose of 50 mg/kg,once a day for 3 consecutive days.Ginsenoside Rc was intragastrically given at dose of 10,20 and 40 mg/kg.At 1 hour after isoproterenol injection.The contents of CK-MB and troponin T in serum were detected,and myocardial histopathology was performed.The levels of MDA,GSH,IL-1β,TNF-α,Nrf2,GCLC,GCLM,and HO-1 in cardiac tissues were detected.Experiment 3.Male Swiss mice were randomly divided into 4 groups: control group,model group,ginsenoside Rc group and ginsenoside Rc+ML385 group.Mice in model group,ginsenoside Rc group and ginsenoside Rc+ML385 group were injected subcutaneously with isoproterenol at a dose of 50 mg/kg,once a day for 3 consecutive days.Ginsenoside Rc was given by intragastric administration at 1 hour after isoproterenol injection.Meanwhile,ginsenoside Rc+ML385 group was also intraperitoneally injected with ML385 at a dose of 30 mg/ kg.The influence of ML385 on ginsenoside Rc-mediated cardioprotective effect was investigated.Results: In normal mice,ginsenoside Rc had no effect on levels of CK-MB and troponin T.The pathological results showed that the myocardium,myocardium,and epicardium were normal.Compared with control group,CK-MB and troponin T in isoproterenol group were significantly increased(P < 0.05 or P < 0.01),MDA,GSH,IL-1β,and TNF-α levels in myocardium in isoproterenol group were significantly increased(P < 0.01).GSH level in isoproterenol group was decreased(P < 0.01),and the expressions of Nrf2,GCLC,GCLM,and HO-1 were significantly decreased(P < 0.01).Compared with isoproterenol group,CK-MB and troponin T in ginsenoside Rc groups were decreased(P < 0.05 or P < 0.01).Ginsenoside Rc significantly reduced the contents of MDA,IL-1β,and TNF-α in mice of myocardial ischemia(P < 0.05,P < 0.01).Ginsenoside Rc treatment decreased the GSH content(P < 0.01)and increased the expressions of Nrf2,GCLC,GCLM,and HO-1 in myocardium(P < 0.05,P < 0.01).In the control group,the histological structure of myocardium was normal,the integrity of myocardium cells was clear,and no inflammatory cell infiltration was observed.The myocardium in the isoproterenol group showed focal necrosis and myofibrillary fracture with inflammatory cell infiltration.While the histopathological changes of the myocardium in the ginsenoside Rc group were significantly reduced,and the degree of inflammatory cell infiltration,focal necrosis,myofibrillary fracture was reduced.Ginsenoside Rc showed cardioprotective effect.However,co-administration with ML385 reversed ginsenoside Rc-mediated reduction of CK-MB,troponin T(P < 0.05,P < 0.01)and myocardial histopathological changes.Compared with ginsenoside Rc group,ML385 partially attenuated the decrease of MDA mediated by ginsenoside Rc(P < 0.01)and the enhancement of GSH,Nrf2,GCLC,and GCLM(P < 0.05,P < 0.01).Consistent with previous findings,ginsenoside Rc reduced the increase of IL-1β and TNF-α induced by myocardial ischemia compared with isoproterenol group(P < 0.01).Ginsenoside Rc also enhanced the expression of Nrf2 and HO-1 in myocardium(P < 0.05,P < 0.01).However,ML385 not only reversed the ginsenoside Rc-mediated reduction of IL-1β and TNF-α(P < 0.05)but also increases of Nrf2 and HO-1(P < 0.05,P < 0.01).Conclusion: Ginsenoside Rc did not cause myocardial injury.Ginsenoside Rc alleviates myocardial ischemia injury through its antioxidant and anti-inflammatory effects.Innovation: It was first demonstrated that ginsenoside Rc had no effect on myocardium in normal mice.The mechanism of cardioprotective effect of ginsenoside Rc was associated with the antioxidant and anti-inflammatory properties.