Τίτλος:
GCH1 haplotype determines vascular and plasma biopterin availability in
coronary artery disease - Effects on vascular superoxide production and
endothelial function
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Antoniades, Charalambos
Shirodaria, Cheerag
Van Assche, Tim and
Cunnington, Colin
Tegeder, Irmgard
Loetsch, Joern
Guzik,
Tomasz J.
Leeson, Paul
Diesch, Jonathan
Tousoulis, Dimitris
and Stefanadis, Christodoulos
Costigan, Michael
Woolf, Clifford
J.
Alp, Nicholas J.
Channon, Keith M.
Περιοδικό:
Journal of the American College of Cardiology
Εκδότης:
EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC
DOI:
10.1016/j.jacc.2007.12.062
