Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension

Mark W. Geraci, Bifeng Gao, David C. Shepherd, Mark D. Moore, Jay Y. Westcott, Karen A. Fagan, Lori A. Alger, Rubin M. Tuder, Norbert F. Voelkel

Research output: Contribution to journalArticle

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Abstract

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway leading to prostacyclin (PGI2) production. Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels, but the importance of this deficiency for lung vascular remodeling remains unclear. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. To study this hypothesis, transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3.7-kb human surfactant protein-C (SP-C) promoter and the rat PGIS cDNA. Transgenic mice (Tg+) and nontransgenic littermates (Tg-) were subjected to a simulated altitude of 17,000 ft for 5 weeks, and right ventricular systolic pressure (RVSP) was measured. Histology was performed on the lungs. The Tg+ mice produced 2-fold more pulmonary 6-keto prostaglandin F(1α) (PGF(1α) levels than did Tg- mice. After exposure to chronic hypobaric hypoxia, Tg+ mice have lower RVSP than do Tg- mice. Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg+ mice in comparison with vessel wall hypertrophy in the Tg- mice. These studies demonstrate that Tg+ mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia. This has important implications for the pathogenesis and treatment of severe pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)1509-1515
Number of pages7
JournalJournal of Clinical Investigation
Volume103
Issue number11
StatePublished - Jun 1999
Externally publishedYes

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Pulmonary Hypertension
Transgenic Mice
Lung
Prostaglandins F
Ventricular Pressure
Epoprostenol
Blood Pressure
Metabolic Networks and Pathways
Protein C
prostacyclin synthetase
Surface-Active Agents
Hypertrophy
Blood Vessels
Histology
Complementary DNA
Enzymes
Hypoxia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Geraci, M. W., Gao, B., Shepherd, D. C., Moore, M. D., Westcott, J. Y., Fagan, K. A., ... Voelkel, N. F. (1999). Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. Journal of Clinical Investigation, 103(11), 1509-1515.

Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. / Geraci, Mark W.; Gao, Bifeng; Shepherd, David C.; Moore, Mark D.; Westcott, Jay Y.; Fagan, Karen A.; Alger, Lori A.; Tuder, Rubin M.; Voelkel, Norbert F.

In: Journal of Clinical Investigation, Vol. 103, No. 11, 06.1999, p. 1509-1515.

Research output: Contribution to journalArticle

Geraci, MW, Gao, B, Shepherd, DC, Moore, MD, Westcott, JY, Fagan, KA, Alger, LA, Tuder, RM & Voelkel, NF 1999, 'Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension', Journal of Clinical Investigation, vol. 103, no. 11, pp. 1509-1515.
Geraci, Mark W. ; Gao, Bifeng ; Shepherd, David C. ; Moore, Mark D. ; Westcott, Jay Y. ; Fagan, Karen A. ; Alger, Lori A. ; Tuder, Rubin M. ; Voelkel, Norbert F. / Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. In: Journal of Clinical Investigation. 1999 ; Vol. 103, No. 11. pp. 1509-1515.
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