Dual Character Of Flavonoids In Attenuating And Aggravating Ischemia-reperfusion-induced Myocardial Injury

Background:The concept that flavonoids exert cardioprotection against myocardial ischemia-reperfusion(I/R)injury has been acknowledged by the major body of evidence.However,a few of recent study discovers that some flavonoids has cardiotoxic activity,although the underlying mechanism is less understood.Flavonoids have been demonstrated to activate aryl hydrocarbon receptor(Ahr)that is implicated in an array of cell signal processes.Aims:This study examined cardioprotective roles of quercetin(Qu)and?-naphthoflavone(?-NF)in the I/R injury,in the meanwhile explored whether some molecular mechanismsdownstream Ahr mediates the adverse effects of Qu and ?-NF.Methods:An oxygen glucose deprivation/reoxygenation(OGD/R)model of I/R was established in myocardial H9c2 cells in the absence or presence of Qu or P-NF.The cells were exposed to hypoxic conditions(oxygen deprivation,0.5%O2)for 24 h in culture medium deprived of glucose and serum,followed by culture under normoxic conditions(reoxygenation)in normal medium for an additional 24 h.Qu(0.5,5 and 50?M)and ?-NF(0.1,1 and 10?M)were added individually to the cells during the whole process of OGD/R.Results:Both Qu and ?-NF reversed OGD/R-induced overproduction of ROS by increasing cell anti-oxidative capacity and protected the cells from the lethal injury(decreased cell death rate,lactate hydrogenase leakage and caspase-3 activity).Nevertheless,our immuno-cytochemistry,co-immunoprecipitation and western blot assays collectively revealed that Qu and ?-NF engendered the translocation of Ahr from cytoplasm into cell nucleus,where Ahr through dimerizing with the ARNT(Ahr nuclear translocator)blocked it binds to hypoxia-inducible factor(HIF)-la,which inhibited the cardioprotection of HIF-la including the induction of nitric oxide(NO)and vascular endothelial growth factor(VEGF)production.Ahr knockdown recovered the binding of ARNT to HIF-1? and the formation of NO and VEGF.Conclusions:The information obtained in this study suggests dual characters of Qu and ?-NF in the process of myocardial I/R:on the one hand the flavonoids suppress the production of ROS in myocardial H9c2 cells in OGD/R processes and protect the cells from death;one the other hand the flavonoids inhibit HIF-la-mediated transcriptional activation of iNOS and VEGF.