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.

Quercetin glucosides promote ischemia-induced angiogenesis, but do not promote tumor growth

“…Consistent with our observation, many researchers have shown that quercetin glucosides activate endothelial nitric oxide and improve endothelial function (Li et al, 2012;Sanchez et al, 2006;Shen et al, 2012). Murohara et al reported that impaired angiogenesis in eNOS−/− mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF (Murohara et al, 1998).…”

Coumestrol inhibits carotid sinus baroreceptor activity by cAMP/PKA dependent nitric oxide release in anesthetized male rats

“…Previous studies have shown that both eNOS and nNOS (neuronal nitric oxide synthase) could play intrinsic roles in the process of arterial baroreception [27,28]. However, our experiments show that CMT has no effect on nNOS activity in the carotid bifurcation tissue.…”

“…cAMP is a central signaling molecule in a variety of cellular systems. PKA is generally cAMP dependent, and cAMP stimulates eNOS phosphorylation by PKA-dependent mechanisms [27][28][29], suggesting that cAMP is upstream of PKA-mediated eNOS activation. Our results indicate that CMT induced a dosedependent increase in intracellular cAMP and phosphorylation of eNOS.…”

Relationship between Platelet PPARs, cAMP Levels, and P-Selectin Expression: Antiplatelet Activity of Natural Products

“…Meanwhile, quercetin-mediated antiplatelet activity involves PI3K/Akt inactivation, cAMP elevation, and VASP stimulation that, in turn, suppresses MAPK phosphorylations [98]. Intraplatelet cAMP production was quickly increased by quercetin stimulation and probably through the adenylate cyclase signaling pathway [130]. …”