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Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice.
J Pharmacol Exp Ther. 2010 Oct; 335(1):149-54.JP

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.

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Authors+Show Affiliations

Xia N
Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
Daiber A
No affiliation info available
Habermeier A
No affiliation info available
Closs EI
No affiliation info available
Thum T
No affiliation info available
Spanier G
No affiliation info available
Lu Q
No affiliation info available
Oelze M
No affiliation info available
Torzewski M
No affiliation info available
Lackner KJ
No affiliation info available
Münzel T
No affiliation info available
Förstermann U
No affiliation info available
Li H
No affiliation info available

MeSH

AnimalsAntioxidantsApolipoproteins EBiopterinGTP CyclohydrolaseIsoenzymesMaleMalondialdehydeMiceMice, KnockoutMyocardiumNitric Oxide Synthase Type IIIOxidative StressRNAResveratrolReverse Transcriptase Polymerase Chain ReactionStilbenesSuperoxide DismutaseSuperoxidesTyrosine

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20610621

Citation

Xia, Ning, et al. "Resveratrol Reverses Endothelial Nitric-oxide Synthase Uncoupling in Apolipoprotein E Knockout Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 335, no. 1, 2010, pp. 149-54.
Xia N, Daiber A, Habermeier A, et al. Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. J Pharmacol Exp Ther. 2010;335(1):149-54.
Xia, N., Daiber, A., Habermeier, A., Closs, E. I., Thum, T., Spanier, G., Lu, Q., Oelze, M., Torzewski, M., Lackner, K. J., Münzel, T., Förstermann, U., & Li, H. (2010). Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. The Journal of Pharmacology and Experimental Therapeutics, 335(1), 149-54. https://doi.org/10.1124/jpet.110.168724
Xia N, et al. Resveratrol Reverses Endothelial Nitric-oxide Synthase Uncoupling in Apolipoprotein E Knockout Mice. J Pharmacol Exp Ther. 2010;335(1):149-54. PubMed PMID: 20610621.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resveratrol reverses endothelial nitric-oxide synthase uncoupling in apolipoprotein E knockout mice. AU - Xia,Ning, AU - Daiber,Andreas, AU - Habermeier,Alice, AU - Closs,Ellen I, AU - Thum,Thomas, AU - Spanier,Gerrit, AU - Lu,Qing, AU - Oelze,Matthias, AU - Torzewski,Michael, AU - Lackner,Karl J, AU - Münzel,Thomas, AU - Förstermann,Ulrich, AU - Li,Huige, Y1 - 2010/07/07/ PY - 2010/7/9/entrez PY - 2010/7/9/pubmed PY - 2010/10/22/medline SP - 149 EP - 54 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 335 IS - 1 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20610621/Resveratrol_reverses_endothelial_nitric_oxide_synthase_uncoupling_in_apolipoprotein_E_knockout_mice_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20610621 DB - PRIME DP - Unbound Medicine ER -