GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.
GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.
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DOI：
10.1016/j.jacc.2007.12.062
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发表时间：
2008-07-08
影响因子：
24
通讯作者：
Channon, Keith M.
中科院分区：
文献类型：
--
作者：
Antoniades, Charalambos;Shirodaria, Cheerag;Van Assche, Tim;Cunnington, Colin;Tegeder, Irmgard;Loetsch, Joern;Guzik, Tomasz J.;Leeson, Paul;Diesch, Jonathan;Tousoulis, Dimitris;Stefanadis, Christodoulos;Costigan, Michael;Woolf, Clifford J.;Alp, Nicholas J.;Channon, Keith M.
本研究旨在确定内源性四氢生物蝶呤（BH 4）的生物利用度对内皮型一氧化氮合酶（eNOS）偶联，一氧化氮（NO）的生物利用度，和血管超氧化物生成的冠状动脉疾病（CAD）患者的影响。由GCH 1基因编码的GTP-环化水解酶I是BH 4生物合成中的限速酶，BH 4是一种对维持酶促偶联很重要的eNOS辅因子。我们研究了GCH 1基因单倍型、GCH 1表达和生物蝶呤水平之间的关系，以及对内皮功能和血管超氧化物生成的影响。从接受冠状动脉旁路移植术的CAD患者（n = 347）中获得血液样本和内乳动脉和隐静脉段。GCH 1单倍型由3个多态性定义：rs 8007267 G <A，rs3783641 A <T和rs 10483639 C <G（X单倍型：A，T，G; O单倍型：任何其他组合）。血管超氧化物（± eNOS抑制剂NG-硝基-L-精氨酸甲酯[L-NAME]）通过光泽精增强化学发光法测定，而隐静脉对乙酰胆碱的血管舒张作用则在体外进行评价。单倍型频率为OO 70.6%，XO 27.4%，XX 2.0%。X单倍型与血管GCH 1信使核糖核酸表达显著降低以及血浆和血管BH 4水平显著降低相关。在X单倍型载体血管超氧化物和L-NAME-可降解的超氧化物显着增加，并与减少血管舒张乙酰胆碱。GCH 1基因表达，由一个特定的GCH 1单倍型调制，是一个主要的决定因素，BH 4的生物利用度在血浆和血管壁的CAD患者。GCH 1的遗传变异是内源性BH 4可用性的重要差异的基础，并且是人类血管疾病中eNOS偶联、血管氧化还原状态和内皮功能的决定因素。
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). 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. 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. 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. 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.
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DOI：
10.1006/bbrc.1998.9942
发表时间：
1999-01-19
影响因子：
3.1
作者：
Skatchkov, MP;Sperling, D;Münzel, T
通讯作者：
Münzel, T
影响因子：
37.8
作者：
Antoniades, Charalambos;Shirodaria, Cheerag;Channon, Keith M.
通讯作者：
Channon, Keith M.
影响因子：
15.9
作者：
Landmesser, U;Dikalov, S;Harrison, DG
通讯作者：
Harrison, DG
影响因子：
4.8
作者：
Kuzkaya, N;Weissmann, N;Dikalov, S
通讯作者：
Dikalov, S
影响因子：
20.1
作者：
Huang, AN;Zhang, YY;Keaney, JF
通讯作者：
Keaney, JF