Red wine polyphenol-induced, endothelium-dependent NO-mediated relaxation is due to the redox-sensitive PI3-kinase/Akt-dependent phosphorylation of endothelial NO-synthase in the isolated porcine coronary artery.
An enhanced endothelial formation of nitric oxide (NO) by red wine polyphenolic compounds (RWPs) has been involved in the protective effect of chronic intake of red wine on coronary diseases. However, the mechanism underlying the activation of endothelial NO synthase (eNOS) remains unclear. In the presence of indomethacin and charybdotoxin plus apamin to prevent the formation of prostanoids and endothelium-derived hyperpolarizing factor, respectively, RWPs caused pronounced endothelium-dependent relaxations in porcine coronary arteries. Relaxations to RWPs were abolished by N(omega)-nitro-L-arginine (L-NA, a competitive inhibitor of NO synthase) and the membrane permeant analog of superoxide dismutase (SOD), MnTMPyP, and reduced by polyethylene glycol-SOD (PEG-SOD), PEG-catalase and inhibitors of PI3-kinase (wortmannin and LY294002). RWPs caused the L-NA-sensitive formation of NO, as assessed by electron spin resonance spectroscopy and the formation of cyclic guanosine monophosphate in coronary artery endothelial cells; these responses were reduced by MnTMPyP, PEG-catalase, and inhibitors of PI3-kinase. RWPs caused the sustained phosphorylation of Akt and eNOS at Ser1177 in endothelial cells, which were abolished by MnTMPyP and inhibitors of PI3-kinase. These data demonstrate that RWPs induce the redox-sensitive activation of the PI3-kinase/Akt pathway in endothelial cells which, in turn, causes phosphorylation of eNOS, resulting in an increased formation of NO.
Ndiaye
Mamadou
M
Pharmacologie et Physico-Chimie des Interactions Cellulaires et Moléculaires, UMR CNRS 7034, Faculté de Pharmacie, Université Louis Pasteur de Strasbourg, Strasbourg, France.
Chataigneau
Marta
M
Lobysheva
Irina
I
Chataigneau
Thierry
T
Schini-Kerth
Valérie B
VB
D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D008665:Metalloporphyrins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D010084:Oxidation-Reduction; D010636:Phenols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000494:pharmacology; D059808:Polyphenols; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013482:Superoxide Dismutase; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014920:Wine / Q000032:analysis*
D002374:Catalase; D006152:Cyclic GMP; D004791:Enzyme Inhibitors; D005419:Flavonoids; D008665:Metalloporphyrins; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols; D059808:Polyphenols; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013482:Superoxide Dismutase; C070295:catalase-polyethylene glycol; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex