Salidroside And SIRT1 Protect Against DOX-induced Cardiac Injury And Molecular Mechanisms

Doxorubicin(DOX)is efficient broad-spectrum anti-cancer antibiotics,which widely used in clinical anthraquinone.However,it has a strong cardiac toxicity,which leads to left ventricular systolic dysfunction and chronic dilated heart failure(CHF)or even death.Thus,DOX is greatly limited for clinical application.Whereas DOX-induced cardiotoxicity due to oxidative stress.Salidroside(SLD)acts as an anti-oxidation drug,which extract from R.hodiola Sachalinensis.Previous research reports that SLD plays an protective role in myocardial ischemia/reperfusion injury,hypoxic injury and hydrogen peroxide-induced oxidative injury,with strong anti-oxidation,anti-apoptotic effects.Protective effect of SLD in DOX-induced myocardial oxidative stress injury has not been elucidated.SIRT1(Sirtuin 1)is a human endogenous deacetylase,which can regulate transcription factors and levels of the target protein through its deacetylase function.Prior studies have shown that SIRT1 plays an important protective role in myocardial ischemia/reperfusion injury and myocardial hypertrophy injury.SIRT1 can regulate the transcription factor to resist oxidative and apoptosis,including p53,FoxO family,MEFs etc.The protective effect of SIRT1 in DOX-induced cardiac injury and its molecular mechanisms have not been elucidated.In this study,we build the DOX-induced cardiotoxicity model in vitro and in vivo.We try to explain the protective effects of SLD on DOX-induced cardiotoxicity through giving SLD to DOX-treated mice or cells.And,we also study the protective effects of SIRT1 on DOX-induced cardiotoxicity through giving DOX to SIRT1 koncked down mice or cells.The following resules:1.SLD improves DOX-impaired mice including survival rate,weight,heart function,myocardial cell atrophy,myocardial fibrosis,myocardial apoptosis and oxidative stress;2.SLD improves DOX-impaired H9c2 cells including cell viability,apoptosis,necrosis and oxidative stress;3.SLD reduces DOX-induced oxidative stress through upregulating catalase and Mn-SOD;4.SLD reduces DOX-induced apoptosis through upregulation of Bcl2/Bax ratios;5.SIRT1 knockout enhances DOX-induced heart function,myocardial fibrosis,myocardial apoptosis and oxidative stress in mice;6.SIRT1 knock enhances DOX-impaired cell viability,apoptosis,necrosis and oxidative stress in cells;7.SIRT1 knockout regulates DOX-impaired AMPK-Fox03a,Fox03a acetylation and Fox03a-p53 complex signaling pathways8.SIRT1 knockout reducesDOX-impaired catalase and Mn-SOD in...