GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease

Antoniades, C. et al. (2008) GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease. Journal of the American College of Cardiology, 52(2), pp. 158-165. (doi: 10.1016/j.jacc.2007.12.062) (PMID:18598896) (PMCID:PMC2699614)

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Objectives: This study sought to determine the effects of endogenous tetrahydrobiopterin (BH4) bioavailability on endothelial nitric oxide synthase (eNOS) coupling, nitric oxide (NO) bioavailability, and vascular superoxide production in patients with coronary artery disease (CAD). Background: GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling. We examined the associations between haplotypes of the GCH1 gene, GCH1 expression and biopterin levels, and the effects on endothelial function and vascular superoxide production. Methods: Blood samples and segments of internal mammary arteries and saphenous veins were obtained from patients with CAD undergoing coronary artery bypass grafting (n = 347). The GCH1 haplotypes were defined by 3 polymorphisms: rs8007267G<A, rs3783641A<T, and rs10483639C<G (X haplotype: A, T, G; O haplotype: any other combination). Vascular superoxide (± the eNOS inhibitor NG-nitro-L-arginine methyl ester [L-NAME]) was measured by lucigenin-enhanced chemiluminescence, whereas the vasorelaxations of saphenous veins to acetylcholine were evaluated ex vivo. Results: Haplotype frequencies were OO 70.6%, XO 27.4%, and XX 2.0%. The X haplotype was associated with significantly lower vascular GCH1 messenger ribonucleic acid expression and substantial reductions in both plasma and vascular BH4 levels. In X haplotype carriers both vascular superoxide and L-NAME–inhibitable superoxide were significantly increased, and were associated with reduced vasorelaxations to acetylcholine. Conclusions: GCH1 gene expression, modulated by a particular GCH1 haplotype, is a major determinant of BH4 bioavailability both in plasma and in the vascular wall in patients with CAD. Genetic variation in GCH1 underlies important differences in endogenous BH4 availability and is a determinant of eNOS coupling, vascular redox state, and endothelial function in human vascular disease.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Guzik, Professor Tomasz
Authors: Antoniades, C., Shirodaria, C., Van Assche, T., Cunnington, C., Tegeder, I., Lötsch, J., Guzik, T. J., Leeson, P., Diesch, J., Tousoulis, D., Stefanadis, C., Woolf, C. J., Alp, N. J., Channon, K. M., and Costigan, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier Inc.
ISSN (Online):1558-3597
Published Online:01 July 2008

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