Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension.

Prostacyclin is a powerful vasodilator and inhibits platelet adhesion and cell growth. We hypothesized that a decrease in expression of the critical enzyme PGI2 synthase (PGI2-S) in the lung may represent an important manifestation of pulmonary endothelial dysfunction in severe pulmonary hypertension (PH). Immunohistochemistry and Western blot analysis were used to assess lung PGI2-S protein expression, and in situ hybridization was used to assess PGI2-S mRNA expression. In the normal pulmonary circulation (n = 7), PGI2-S was expressed in 48% of small, 67% of medium, and 76% of large pulmonary arteries as assessed by immunohistochemistry. PPH (n = 12), cirrhosis-associated (n = 4) and HIV-associated PH (n = 2) lungs exhibited a marked reduction in PGI2-S expression, involving all size ranges of pulmonary arteries. Vessels with concentric lesions showed complete lack of PGI2-S expression. Congenital heart (n = 4) and CREST (n = 2) cases exhibited a more variable immunohistological pattern of PGI2-S expression. These results were complemented by in situ hybridization and Western blots of representative lung samples. We conclude that the different sizes of the pulmonary arteries express PGI2-S differently and that the loss of expression of PGI2-S represents one of the phenotypic alterations present in the pulmonary endothelial cells in severe PH.

[1]  S. Archer,et al.  Increased endothelium-derived NO in hypertensive pulmonary circulation of chronically hypoxic rats. , 1994, Journal of applied physiology.

[2]  A Giaid,et al.  Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. , 1995, The New England journal of medicine.

[3]  D. Stewart,et al.  Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. , 1993, The New England journal of medicine.

[4]  Y. Miller,et al.  Novel bombesin-like peptide binding proteins from lung. , 1994, American journal of respiratory cell and molecular biology.

[5]  N. E. Owen.  Prostacyclin Can Inhibit DNA Synthesis in Vascular Smooth Muscle Cells , 1985 .

[6]  C. Wagenvoort,et al.  Primary Pulmonary Hypertension: A Pathologic Study of the Lung Vessels in 156 Clinically Diagnosed Cases , 1970 .

[7]  L. Wang,et al.  Bovine prostacyclin synthase: purification and isolation of partial cDNA. , 1993, Biochemical and biophysical research communications.

[8]  R. Johns,et al.  Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. , 1995, The New England journal of medicine.

[9]  N. Voelkel,et al.  Moderation of hypoxic vasoconstriction by infused arachidonic acid: role of PGI2. , 1980, Journal of applied physiology: respiratory, environmental and exercise physiology.

[10]  R. Brugger,et al.  Characterization of monoclonal antibodies generated against bovine and porcine prostacyclin synthase and quantitation of bovine prostacyclin synthase , 1994, FEBS letters.

[11]  N. Voelkel,et al.  Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. , 1997, Human pathology.

[12]  N. Voelkel,et al.  Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline. , 1994, American journal of respiratory cell and molecular biology.

[13]  L. Reid,et al.  Control of cell proliferation in pulmonary hypertension , 1989 .

[14]  R. Winter.  MONITORING THE CIRCLE SYSTEM : THE EUROPEAN PERSPECTIVE , 1995 .

[15]  B. Koller,et al.  Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. , 1996, The Journal of clinical investigation.

[16]  A. Halbower,et al.  Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. , 1997, The American journal of physiology.

[17]  N. D. Arnold,et al.  Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32 , 1997, Nature Genetics.

[18]  M. Yacoub,et al.  High expression of endothelial nitric oxide synthase in plexiform lesions of pulmonary hypertension , 1998, The Journal of pathology.

[19]  D. Dewitt,et al.  Bimodal distribution of the prostaglandin I2 synthase antigen in smooth muscle cells. , 1983, The Journal of biological chemistry.

[20]  A. Halbower,et al.  Agarose infiltration improves morphology of cryostat sections of lung. , 1994, Laboratory investigation; a journal of technical methods and pathology.

[21]  D. Badesch,et al.  Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. , 1989, American journal of respiratory cell and molecular biology.

[22]  N. Voelkel,et al.  5-Lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. , 1998, American journal of respiratory and critical care medicine.

[23]  W. Campbell,et al.  Stimulation of prostaglandin formation by vasoactive mediators in cultured human endothelial cells. , 1982, Prostaglandins.

[24]  K. Shroyer,et al.  Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. , 1998, The Journal of clinical investigation.

[25]  B. Groves,et al.  Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. , 1994, The American journal of pathology.

[26]  T. Ogihara,et al.  Overexpression of prostacyclin synthase inhibits growth of vascular smooth muscle cells. , 1995, Biochemical and biophysical research communications.

[27]  J. Loscalzo.  Endothelial dysfunction in pulmonary hypertension. , 1992, The New England journal of medicine.

[28]  B. Groves,et al.  An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. , 1992, The New England journal of medicine.

[29]  R. Johns,et al.  Chronic hypoxia upregulates endothelial and inducible NO synthase gene and protein expression in rat lung. , 1996, The American journal of physiology.