title: Quercetin induces rapid eNOS phosphorylation and vasodilation by an Akt-independent and PKA-dependent mechanism.
abstract: Consumption of the flavonoid quercetin exerts beneficial effects on many chronic diseases. The mechanisms involved in the vasorelaxant effect of quercetin remain uncertain. In the present study, we examined the role of quercetin in vasodilation and rapid endothelial nitric oxide synthase (eNOS) activity in endothelial cells. Quercetin induced a rapid, dose-dependent phosphorylation of eNOS at serine 1179. PKA, Akt and ERK1/2 were all quickly phosphorylated in the process too, but not AMPK and CaMK II. The specific kinase inhibitors for Akt or ERK1/2 could not abolish the quercetin-induced eNOS phosphorylation at Ser1179, which, however, was significantly abolished by H89, an inhibitor of PKA. Concomitantly, intracellular cAMP production was quickly increased by quercetin stimulation and an adenylate cyclase activator, forskolin, also induced eNOS phosphorylation at Ser1179. Quercetin enhanced nitric oxide (NO) production, which was abolished by an eNOS inhibitor, L-NAME or H89. Quercetin exerted a vasodilatory effect on rings with an intact endothelium but not on endothelium-deprived rings, and also inhibited vascular contractility induced by angiotensin II or phenylephrine in rat aortic rings. We conclude that quercetin quickly phosphorylates eNOS at Ser1179 via an Akt-independent, cAMP/PKA-mediated pathway to enhance the production of NO and to promote vasodilation.
authors.affiliation: Department of Nutrition and Food Hygiene, Capital Medical University School of Public Health and Family Medicine, Beijing, PR China.
authors.forename: Peng-Gao
authors.initials: PG
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.forename: Shuang
authors.initials: S
authors.lastname: Ling
authors.forename: Wo-Ting
authors.initials: WT
authors.lastname: Gan
authors.forename: Jin-Wen
authors.initials: JW
authors.lastname: Xu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D009569:Nitric Oxide; D011794:Quercetin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases