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Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin.
Free Radic Biol Med. 2004 Jun 15; 36(12):1532-41.FR

Abstract

Hyperhomocysteinemia is a risk factor for cardiovascular diseases that induces endothelial dysfunction. Here, we examine the participation of endothelial NO synthase (eNOS) in the homocysteine-induced alterations of NO/O(2)(-) balance in endothelial cells from human umbilical cord vein. When cells were treated for 24 h, homocysteine dose-dependently inhibited thrombin-activated NO release without altering eNOS phosphorylation and independently of the endogenous NOS inhibitor, asymmetric dimethylarginine. The inhibitory effect of homocysteine on NO release was associated with increased production of reactive nitrogen and oxygen species (RNS/ROS) independent of extracellular superoxide anion (O(2)(-)) and was suppressed by the NOS inhibitor L-NAME. In unstimulated cells, L-NAME markedly decreased RNS/ROS formation and the ethidium red fluorescence induced by homocysteine. This eNOS-dependent O(2)(-) synthesis was associated with reduced intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (-80%) and increased release of 7,8-dihydrobiopterin and biopterin in the extracellular medium (+40%). In addition, homocysteine suppressed the activating effect of sepiapterin on NO release, but not that of ascorbate. The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability.

Authors+Show Affiliations

Topal G
Département de Signalisation cellulaire et athérosclérose précoce, UMR CNRS 7131- Université Paris 6, Hôpital Broussais, 102 rue Didot, 75014 Paris, France.
Brunet A
No affiliation info available
Millanvoye E
No affiliation info available
Boucher JL
No affiliation info available
Rendu F
No affiliation info available
Devynck MA
No affiliation info available
David-Dufilho M
No affiliation info available

MeSH

AntioxidantsArginineAscorbic AcidBiopterinBlotting, WesternCells, CulturedDose-Response Relationship, DrugEndothelium, VascularEthidiumFluorescent DyesHomocysteineHumansL-Lactate DehydrogenaseNG-Nitroarginine Methyl EsterNitric OxideNitric Oxide SynthaseNitric Oxide Synthase Type IIIOxidative StressPhosphorylationPterinsReactive Nitrogen SpeciesSuperoxidesThrombinTime Factors

Pub Type(s)

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

Language

eng

PubMed ID

15182855

Citation

Topal, Gökce, et al. "Homocysteine Induces Oxidative Stress By Uncoupling of NO Synthase Activity Through Reduction of Tetrahydrobiopterin." Free Radical Biology & Medicine, vol. 36, no. 12, 2004, pp. 1532-41.
Topal G, Brunet A, Millanvoye E, et al. Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic Biol Med. 2004;36(12):1532-41.
Topal, G., Brunet, A., Millanvoye, E., Boucher, J. L., Rendu, F., Devynck, M. A., & David-Dufilho, M. (2004). Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radical Biology & Medicine, 36(12), 1532-41.
Topal G, et al. Homocysteine Induces Oxidative Stress By Uncoupling of NO Synthase Activity Through Reduction of Tetrahydrobiopterin. Free Radic Biol Med. 2004 Jun 15;36(12):1532-41. PubMed PMID: 15182855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. AU - Topal,Gökce, AU - Brunet,Annie, AU - Millanvoye,Elisabeth, AU - Boucher,Jean-Luc, AU - Rendu,Francine, AU - Devynck,Marie-Aude, AU - David-Dufilho,Monique, PY - 2004/01/12/received PY - 2004/03/17/revised PY - 2004/03/26/accepted PY - 2004/6/9/pubmed PY - 2005/1/14/medline PY - 2004/6/9/entrez SP - 1532 EP - 41 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 36 IS - 12 N2 - Hyperhomocysteinemia is a risk factor for cardiovascular diseases that induces endothelial dysfunction. Here, we examine the participation of endothelial NO synthase (eNOS) in the homocysteine-induced alterations of NO/O(2)(-) balance in endothelial cells from human umbilical cord vein. When cells were treated for 24 h, homocysteine dose-dependently inhibited thrombin-activated NO release without altering eNOS phosphorylation and independently of the endogenous NOS inhibitor, asymmetric dimethylarginine. The inhibitory effect of homocysteine on NO release was associated with increased production of reactive nitrogen and oxygen species (RNS/ROS) independent of extracellular superoxide anion (O(2)(-)) and was suppressed by the NOS inhibitor L-NAME. In unstimulated cells, L-NAME markedly decreased RNS/ROS formation and the ethidium red fluorescence induced by homocysteine. This eNOS-dependent O(2)(-) synthesis was associated with reduced intracellular levels of both total biopterins (-45%) and tetrahydrobiopterin (-80%) and increased release of 7,8-dihydrobiopterin and biopterin in the extracellular medium (+40%). In addition, homocysteine suppressed the activating effect of sepiapterin on NO release, but not that of ascorbate. The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/15182855/Homocysteine_induces_oxidative_stress_by_uncoupling_of_NO_synthase_activity_through_reduction_of_tetrahydrobiopterin_ DB - PRIME DP - Unbound Medicine ER -