Prostacyclin Synthase Expression Is Decreased in Lungs from Patients with Severe Pulmonary Hypertension

Abstract

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.

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

“…23 Our observation of a "dysfunctional HDL pheno- type" may partially explain the abnormally reduced PGI 2 generation that is pivotal in the pathogenesis and treatment of experimental and clinical PAH. [24][25][26][27][28] Further, in studies of pleiotropic HMG CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase inhibitor medications ("statins") which, despite effectuating a reduction in "oxidant stress," a reduction in Rho/Rho-kinase (ROCK) signaling, enhanced endothelial nitric oxide production, and increased expression of bone morphogenetic protein receptor type 2, have been disappointing in both the treatment of PAH and experimental models of vascular PGI 2 production. [29][30][31][32][33][34] "Oxidant stress" has been reported in PAH by Cracowski et al, 35 who described increased isoprostane urinary levels that correlated with worsened patient survival.…”

Pathology of Pulmonary Hypertension

“…These lesions have decreased expression of anti-remodeling mediators such as nitric oxide synthase [35] and prostacyclin synthase [36], and tumor suppressors, such as caveolin-1 [37]. These phenotypic characteristics lead us to propose that the plexiform lesions have characteristics in common with neoplasms [38].…”

Grape Seed Procyanidin Extract Mediates Antineoplastic Effects against Lung Cancer via Modulations of Prostacyclin and 15-HETE Eicosanoid Pathways

“…A majority of NSCLCs have decreased PGIS expression (13). The potential of oral iloprost, a synthetic analogue of PGI 2 , as a chemopreventive agent for lung cancer has been evaluated in a multicenter phase IIb study.…”