GCH1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery DiseaseEffects on Vascular Superoxide Production and Endothelial Function
Charalambos Antoniades, MD, PhD*,
Cheerag Shirodaria, MRCP*,
Tim Van Assche, PhD*,
Colin Cunnington, MRCP*,
Irmgard Tegeder, MD, PhD , ,
Jörn Lötsch, MD, PhD,
Tomasz J. Guzik, MD, PhD*, ,
Paul Leeson, MRCP, PhD*,
Jonathan Diesch, HNC*,
Dimitris Tousoulis, MD, PhD, FACC¶,
Christodoulos Stefanadis, MD, FACC, FESC¶,
Michael Costigan, PhD,
Clifford J. Woolf, MD, PhD,
Nicholas J. Alp, MD, PhD, MRCP* and
Keith M. Channon, MD, FRCP*,*
* Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
Pharmazentrum Frankfurt/ZAFES, Institute for Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt am Main, Germany
Departments of Medicine and Pharmacology, Jagiellonian University, Cracow, Poland
¶ Athens University Medical School, 1st Cardiology Department, Hippokration Hospital, Athens, Greece.
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Figure 1 Effect of GCH1 Haplotype on Plasma/Vascular BH4
The presence of the haplotype (XO or XX) was associated with significantly lower levels of plasma tetrahydrobiopterin (BH4) (A) and total biopterins (tBio) (B). A similar effect was also observed in saphenous veins (SV) (C and D) and internal mammary arteries (IMA) (E and F).
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Figure 2 Effect of GCH1 Haplotype on Vascular GTPCH mRNA Levels
The presence of the XX genotype was associated with significantly lower messenger ribonucleic acid (mRNA) levels of GTPCH compared with OO genotype. Shown are the data derived from 23 saphenous veins (SVs) and 17 internal mammary arteries (IMAs). *p < 0.05 versus OO.
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Figure 3 Effect of GCH1 Haplotype on Vascular Superoxide, Oxidative Stress, and Endothelial Function
The presence of the X haplotype was associated with higher total superoxide (O2
–) production (A) and greater L-NAME-inhibitable delta[O2
–] (B) in human saphenous veins. The X haplotype was also associated with significantly lower plasma BH4:tBio ratio (C) and higher plasma levels of oxidized low-density lipoprotein (ox-LDL) (D). In addition, the X haplotype was also associated with lower maximum vasorelaxations in response to acetylcholine (ACh) (E) in saphenous veins, although it had no impact on the vasomotor responses to sodium nitroprusside (SNP) (F).
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