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Romero M, Jimenez R, Sánchez M, López-Sepúlveda R, Zarzuelo MJ, O'Valle F, Zarzuelo A, Perez-Vizcaino F, Duarte J

Quercetin inhibits vascular superoxide production induced by endothelin-1: Role of NADPH oxidase, uncoupled eNOS and PKC.

Atherosclerosis. 2009 Jan;202(1):58-67, PMID: 18436224

Chronic administration of the most abundant dietary flavonoid quercetin exerts antihypertensive effects and improves endothelial function. We have investigated the effects of quercetin and its methylated metabolite isorhamnetin (1-10microM) on endothelial dysfunction and superoxide (O(2*)(-)) production induced by endothelin-1 (ET-1, 10nM). ET-1 increased the contractile response induced by phenylephrine and reduced the relaxant responses to acetylcholine in phenylephrine contracted intact aorta, and these effects were prevented by co-incubation with quercetin, isorhamnetin or chelerythrine (protein kinase C (PKC) inhibitor). This endothelial dysfunction was also improved by superoxide dismutase (SOD), apocynin (NADPH oxidase inhibitor) and sepiapterin (tetrahydrobiopterin synthesis substrate). Furthermore, ET-1 increased intracellular O(2*)(-) production in all layers of the vessel, protein expression of NADPH oxidase subunit p47(phox) without affecting p22(phox) expression and lucigenin-enhanced chemiluminescence signal stimulated by calcium ionophore A23187. All these changes were prevented by both quercetin and isorhamnetin. Moreover, apocynin, endothelium denudation and N(G)-nitro-l-arginine methylester (l-NAME, nitric oxide synthase inhibitor) suppressed the ET-1-induced increase in A23187-stimulated O(2*)(-) generation. Moreover, quercetin but not isorhamnetin, inhibited the increased PKC activity induced by ET-1. Taken together these results indicate that ET-1-induced NADPH oxidase up-regulation and eNOS uncoupling via PKC leading to endothelial dysfunction and these effects were prevented by quercetin and isorhamnetin.

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