Quercetin Inhibited Endothelial Dysfunction and Atherosclerosis in Apolipoprotein E-Deficient Mice: Critical Roles for NADPH Oxidase and Heme Oxygenase-1

NADPH oxidase-dependent superoxide (O₂^·-) production and oxidative stress play important roles in endothelial dysfunction and atherosclerosis. Herein, we investigated the potential effects of dietary quercetin, a flavonoid derived in the diet from vegetables and fruit, on vascular endothelial function and atherosclerosis in the high-fat diet (HFD)-fed apolipoprotein E-deficient (ApoE^-/-) mice. Dietary quercetin treatment significantly suppressed endothelial dysfunction and aortic atherosclerosis in HFD-fed ApoE^-/- mice (P < 0.05, all cases). Mechanistic studies demonstrated that dietary quercetin significantly attenuated p47phox expression and inhibited NADPH oxidase-derived oxidative stress in the aortas of HFD-fed ApoE^-/- mice, while the expression and activity of antioxidant enzyme heme oxygenase-1 (HO-1) was enhanced after quercetin treatment (P < 0.05, all cases). In vitro, it was found that quercetin significantly attenuated NADPH oxidase-derived O₂^·- formation (75 ± 5.6% for quercetin versus 100 ± 6.0% for the control group, P < 0.01) in endothelial cells through induction of HO-1. In addition, the favorable effects of quercetin on oxidant (i.e., H₂O₂)-induced endothelial dysfunction could be eliminated by tin protoporphyrin IX (an HO-1 inhibitor) or HO-1-specific siRNA. Our results demonstrated the critical roles of NADPH oxidase and HO-1 for the indirect antioxidant properties of quercetin in vascular diseases.