Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse.
BACKGROUND
GTP-cyclohydrolase 1 (GTP-CH1) catalyzes the first step for the de novo production of tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthase (NOS). The hyperphenylalaninemic mutant mouse (hph-1) displays a 90% reduction in GTP-CH1 activity. Reduced BH4 decreases NOS activity and may lead to endothelial dysfunction, and there is increasing evidence that a dysfunction of the NOS pathway may be implicated in pulmonary hypertension. The aim of the study was to investigate whether reduced BH4 in the hph-1 mouse results in a pulmonary hypertensive phenotype.


RESULTS
Morphological characterization of the heart, lung, and kidney and measurements of systemic and right ventricular blood pressures were performed in both hph-1 and wild-type mice. BH4 and NO(x) levels were also measured. Hph-1 mice had significantly lower NO(x) and BH4 levels, consistent with previous findings. Both morphological and in vivo data were indicative of a pulmonary but not systemic hypertensive phenotype. We observed increased right ventricle-left ventricle plus septum ratios attributable only to an increase in right ventricular mass, increased smooth muscle medial area in pulmonary resistance vessels, and significantly higher right ventricular pressures in vivo. There were no significant differences between left ventricular masses and systemic pressures, and there was no observed evidence of systemic hypertension in kidney sections between wild-type and hph-1.


CONCLUSIONS
This study demonstrates that mice deficient in GTP-CH1/BH4 display a pulmonary hypertensive but not systemic hypertensive phenotype.
Nandi
Manasi
M
Centre for Clinical Pharmacology, British Heart Foundation Laboratories, The Rayne Institute, University College London, 5 University St, London WC1E 6JJ, United Kingdom. m.nandi@ucl.ac.uk
Miller
Alyson
A
Stidwill
Raymond
R
Jacques
Thomas S
TS
Lam
Amanda A J
AA
Haworth
Sheila
S
Heales
Simon
S
Vallance
Patrick
P
D000818:Animals; D001158:Arteries / Q000473:pathology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006136:GTP Cyclohydrolase / Q000172:deficiency*; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009569:Nitric Oxide / Q000032:analysis; D011652:Pulmonary Circulation; D014655:Vascular Resistance
D001708:Biopterins; D009569:Nitric Oxide; D006136:GTP Cyclohydrolase; C003402:sapropterin