title: Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice.
abstract: A crucial cause of the decreased bioactivity of nitric oxide (NO) in cardiovascular diseases is the uncoupling of the endothelial NO synthase (eNOS) caused by the oxidative stress-mediated deficiency of the NOS cofactor tetrahydrobiopterin (BH(4)). The reversal of eNOS uncoupling might represent a novel therapeutic approach. The treatment of apolipoprotein E knockout (ApoE-KO) mice with resveratrol resulted in the up-regulation of superoxide dismutase (SOD) isoforms (SOD1-SOD3), glutathione peroxidase 1 (GPx1), and catalase and the down-regulation of NADPH oxidases NOX2 and NOX4 in the hearts of ApoE-KO mice. This was associated with reductions in superoxide, 3-nitrotyrosine, and malondialdehyde levels. In parallel, the cardiac expression of GTP cyclohydrolase 1 (GCH1), the rate-limiting enzyme in BH(4) biosynthesis, was enhanced by resveratrol. This enhancement was accompanied by an elevation in BH(4) levels. Superoxide production from ApoE-KO mice hearts was reduced by the NOS inhibitor L-N(G)-nitro-arginine methyl ester, indicating eNOS uncoupling in this pathological model. Resveratrol treatment resulted in a reversal of eNOS uncoupling. Treatment of human endothelial cells with resveratrol led to an up-regulation of SOD1, SOD2, SOD3, GPx1, catalase, and GCH1. Some of these effects were preventable with sirtinol, an inhibitor of the protein deacetylase sirtuin 1. In summary, resveratrol decreased superoxide production and enhanced the inactivation of reactive oxygen species. The resulting reduction in BH(4) oxidation, together with the enhanced biosynthesis of BH(4) by GCH1, probably was responsible for the reversal of eNOS uncoupling. This novel mechanism (reversal of eNOS uncoupling) might contribute to the protective effects of resveratrol.
authors.affiliation: Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
authors.forename: Alice
authors.initials: A
authors.lastname: Habermeier
authors.forename: Ellen I
authors.initials: EI
authors.lastname: Closs
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
authors.forename: Gerrit
authors.initials: G
authors.lastname: Spanier
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Michael
authors.initials: M
authors.lastname: Torzewski
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Förstermann
authors.forename: Huige
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D007527:Isoenzymes; D013267:Stilbenes; D013481:Superoxides; D001708:Biopterins; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D012313:RNA; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D000077185:Resveratrol