Faculty Collaboration Database

Pulmonary hypertension in the newborn GTP cyclohydrolase I-deficient mouse. Free Radic Biol Med 2011 Dec 15;51(12):2227-33

Date

10/11/2011

Pubmed ID

21982896

Pubmed Central ID

PMC5050525

DOI

10.1016/j.freeradbiomed.2011.09.012

Scopus ID

2-s2.0-81855221784 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

Tetrahydrobiopterin (BH4) is a regulator of endothelial nitric oxide synthase (eNOS) activity. Deficient levels result in eNOS uncoupling, with a shift from nitric oxide to superoxide generation. The hph-1 mutant mouse has deficient GTP cyclohydrolase I (GTPCH1) activity, resulting in low BH4 tissue content. The adult hph-1 mouse has pulmonary hypertension, but whether such condition is present from birth is not known. Thus, we evaluated newborn animals' pulmonary arterial medial thickness, biopterin content (BH4+BH2), H(2)O(2) and eNOS, right ventricle-to-left ventricle+septum (RV/LV+septum) ratio, near-resistance pulmonary artery agonist-induced force, and endothelium-dependent and -independent relaxation. The lung biopterin content was inversely related to age for both types, but significantly lower in hph-1 mice, compared to wild-type animals. As judged by the RV/LV+septum ratio, newborn hph-1 mice have pulmonary hypertension and, after a 2-week 13% oxygen exposure, the ratios were similar in both types. The pulmonary arterial agonist-induced force was reduced (P<0.01) in hph-1 animals and no type-dependent difference in endothelium-dependent or -independent vasorelaxation was observed. Compared to wild-type mice, the lung H(2)O(2) content was increased, whereas the eNOS expression was decreased (P<0.01) in hph-1 animals. The pulmonary arterial medial thickness, a surrogate marker of vascular remodeling, was increased (P<0.01) in hph-1 compared to wild-type mice. In conclusion, our data suggest that pulmonary hypertension is present from birth in the GTPCH1-deficient mice, not as a result of impaired vasodilation, but secondary to vascular remodeling.

Author List

Belik J, McIntyre BA, Enomoto M, Pan J, Grasemann H, Vasquez-Vivar J

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Newborn
Female
GTP Cyclohydrolase
Hypertension, Pulmonary
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA