Dual character of flavonoids in attenuating and aggravating ischemia-reperfusion-induced myocardial injury.

ABSTRACT: The concept that flavonoids exert cardioprotection against myocardial ischemia-reperfusion (I/R) injury has been acknowledged by a large body of evidence. However, recent studies reported cardiotoxic effects of certain flavonoids, while the underlying mechanisms have remained largely elusive. Flavonoids have been demonstrated to activate aryl hydrocarbon receptor (Ahr), which is implicated in an array of cell signaling processes. The present study examined the cardioprotective roles of quercetin (Qu) and β-naphthoflavone (β-NF) against I/R injury and explored whether the underlying mechanism proceeds via molecular signaling downstream of Ahr. 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 β-NF. Qu as well as β-NF reversed OGD/R-induced overproduction of reactive oxygen species by increasing the anti-oxidative capacity of the cells and protected them from lethal injury, as demonstrated by a decreased cell death rate, lactate hydrogenase leakage and caspase-3 activity as determined by flow cytometry, colorimetric assay and western blot analysis, respectively. Immunocytochemistry, co-immunoprecipitation and western blot assays collectively revealed that Qu and β-NF engendered the translocation of Ahr from the cytoplasm into the cell nucleus, where binding of Ahr with the Ahr nuclear translocator (ARNT) blocked its binding to hypoxia-inducible factor (HIF)-1α, which inhibited the cardioprotection of HIF-1α, including the induction of nitric oxide (NO) and inhibition of vascular endothelial growth factor (VEGF) production. Ahr knockdown recovered the binding of ARNT to HIF-1α and the generation of NO and VEGF. The results of the present study suggested a dual character of Qu and β-NF in the process of myocardial I/R.

SUBMITTER: Li W 

PROVIDER: S-EPMC5525640 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other