Peroxisome Proliferator-Activated Receptor ? Mediated Protective Effects Of Quercetin On Myocardial Ischemia-Reperfusion Via NF-?B Pathway

Background and purposeAn acute application of quercetin before ischemia or during reperfusion has been found to protect myocardium from ischemia and reperfusion injury(IRI).However,little is known about the mechanism of this process.In this study,we tested the hypothesis that quercetin protected against myocardial IRI and investigated the underlying molecular mechanisms involved.MethodsIn vivo,quercetin(250mg/kg/day),GW9962(PPAR? antagonist),or combination of both were administered prior to mice myocardial IRI model.In vitro,quercetin was given to myocardial H9C2 cells before hypoxia and reoxygenation(HR)treatment.Meanwhile,PPAR?-specfic siRNA was used to interfere PPAR? expression on H9C2 cells.Cardiac function was measured,and infarct size was evaluated by triphenyltetrazolium chloride(TTC)staining at the end of the reperfusion.Arterial blood was analyzed for aspartate transaminase(AST),creatinine kinase-MB isoenzyme(CK-MB),cardiac troponin T(cTnT)and lactate dehydrogenase(LDH).Oxidative stress injury was also measured by malondialdehyde(MDA),Superoxide dismutase(SOD)and glutathione peroxidase(GSH-PX)in vivo and by inducible nitric oxide synthase(iNOS)and reactive oxygen species(ROS)in vitro.Myocardium apoptosis was reflected by TUNEL staining,caspase-3 expression and Annexin V/PI detection.Moreover,activation of NF-?B pathway was analyzed by phosphorylation of I?B and nuclear translocation of p65.ResultsWe demonstrated that administration of quercetin before myocardial IRI significantly limited infarct size,improved heart contraction and reduced the release of myocardial-specific markers into serum in myocardial IRI mice.Myocardium oxidative stress injury and apoptotic marks remarkably changed in the presence of quercetin as well in vivo and in vitro.Quercetin up-regulated the expression of PPAR? in IRI hearts,while GW9662,the selective PPAR? antagonist,could attenuated the effects of quercetin administration.In H9C2 cells suffered from HR,we detected a high endonuclear expression of p65 and phosphorylated I?B?,however,after treatment of quercetin,the nuclear translocation of p65 and phosphorylation of I?B? was repressed.These effects were partially abolished after PPAR? knockdown by using siRNA,showing the suppressed effect of quercetin on nuclear translocation and transcriptional activity of NF-?B via PPAR?.ConclusionsOur findings suggested that quercetin ameliorated IRI-induced heart damage through PPAR? activation and down-regulation of the NF-?B signaling pathway.