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Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis. 2011

Charalambos Antoniades, and Colin Cunnington, and Alexis Antonopoulos, and Matt Neville, and Marios Margaritis, and Michael Demosthenous, and Jennifer Bendall, and Ashley Hale, and Ruha Cerrato, and Dimitris Tousoulis, and Constantinos Bakogiannis, and Kyriakoula Marinou, and Marina Toutouza, and Charalambos Vlachopoulos, and Paul Leeson, and Christodoulos Stefanadis, and Fredrik Karpe, and Keith M Channon
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Hedley Way, OX3 9DU, Oxford, UK.

BACKGROUND The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) is essential for maintenance of enzymatic function. We hypothesized that induction of BH4 synthesis might be an endothelial defense mechanism against inflammation in vascular disease states. RESULTS In Study 1, 20 healthy individuals were randomized to receive Salmonella typhi vaccine (a model of acute inflammation) or placebo in a double-blind study. Vaccination increased circulating BH4 and interleukin 6 and induced endothelial dysfunction (as evaluated by brachial artery flow-mediated dilation) after 8 hours. In Study 2, a functional haplotype (X haplotype) in the GCH1 gene, encoding GTP-cyclohydrolase I, the rate-limiting enzyme in biopterin biosynthesis, was associated with endothelial dysfunction in the presence of high-sensitivity C-reactive protein in 440 coronary artery disease patients. In Study 3, 10 patients with coronary artery disease homozygotes for the GCH1 X haplotype (XX) and 40 without the haplotype (OO) underwent S Typhi vaccination. XX patients were unable to increase plasma BH4 and had a greater reduction of flow-mediated dilation than OO patients. In Study 4, vessel segments from 19 patients undergoing coronary bypass surgery were incubated with or without cytokines (interleukin-6/tumor necrosis factor-α/lipopolysaccharide) for 24 hours. Cytokine stimulation upregulated GCH1 expression, increased vascular BH4, and improved vasorelaxation in response to acetylcholine, which was inhibited by the GTP-cyclohydrolase inhibitor 2,4-diamino-6-hydroxypyrimidine. CONCLUSIONS The ability to increase vascular GCH1 expression and BH4 synthesis in response to inflammation preserves endothelial function in inflammatory states. These novel findings identify BH4 as a vascular defense mechanism against inflammation-induced endothelial dysfunction.

UI MeSH Term Description Entries
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D004311 Double-Blind Method A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment. Double-Masked Study,Double-Blind Study,Double-Masked Method,Double Blind Method,Double Blind Study,Double Masked Method,Double Masked Study,Double-Blind Methods,Double-Blind Studies,Double-Masked Methods,Double-Masked Studies,Method, Double-Blind,Method, Double-Masked,Methods, Double-Blind,Methods, Double-Masked,Studies, Double-Blind,Studies, Double-Masked,Study, Double-Blind,Study, Double-Masked
D004730 Endothelium, Vascular Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components. Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D005260 Female Females
D006136 GTP Cyclohydrolase (GTP cyclohydrolase I) or GTP 7,8-8,9-dihydrolase (pyrophosphate-forming) (GTP cyclohydrolase II). An enzyme group that hydrolyzes the imidazole ring of GTP, releasing carbon-8 as formate. Two C-N bonds are hydrolyzed and the pentase unit is isomerized. This is the first step in the synthesis of folic acid from GTP. EC 3.5.4.16 (GTP cyclohydrolase I) and EC 3.5.4.25 (GTP cyclohydrolase II). GTP 8-Formylhydrolase,GTP Dihydrolase,GTP Ring-Opening Enzyme,7,8-Dihydroneopterintriphosphate Synthetase,GTP Cyclohydrolase I,GTP Cyclohydrolase II,7,8 Dihydroneopterintriphosphate Synthetase,8-Formylhydrolase, GTP,Cyclohydrolase I, GTP,Cyclohydrolase II, GTP,Cyclohydrolase, GTP,Dihydrolase, GTP,GTP 8 Formylhydrolase,GTP Ring Opening Enzyme,Ring-Opening Enzyme, GTP,Synthetase, 7,8-Dihydroneopterintriphosphate
D006239 Haplotypes The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX. Haplotype
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults

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