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.
Tuder
R M
RM
Departments of Pathology, Medicine (Division of Pulmonary Sciences and Critical Care Medicine), Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Cool
C D
CD
Geraci
M W
MW
Wang
J
J
Abman
S H
SH
Wright
L
L
Badesch
D
D
Voelkel
N F
NF
D000328:Adult; D015153:Blotting, Western; D017675:CREST Syndrome / Q000150:complications; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000150:complications; D006330:Heart Defects, Congenital / Q000150:complications; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000201:enzymology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000150:complications; D008168:Lung / Q000201:enzymology*; D008297:Male; D008875:Middle Aged
D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase