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

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

doi:10.1172/jci5911

Cited by 205 publications

(138 citation statements)

References 29 publications

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“…In contrast, PGE2 is proinflammatory, induces proliferation, and is antiapoptotic (5). Results from our work and others have highlighted the importance of balance in PGI2 and PGE2 levels in pulmonary diseases, such as pulmonary hypertension and chronic obstructive pulmonary disease (6).…”

Section: Introductionsupporting

confidence: 55%

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Stearman

Grady

Nana‐Sinkam

et al. 2007

Molecular Cancer Research

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The importance of the arachidonic acid pathway has been established in colon and lung cancers, as well as in inflammatory diseases. In these diseases, prostacyclin I 2 (PGI2) and prostaglandin E 2 (PGE2) are thought to have antagonistic activities, with PGI2 exerting anti-inflammatory and antiproliferative activities, whereas PGE2 is proinflammatory and antiapoptotic. In human lung cancer, prostacyclin synthase (PGIS) and PGI2 are down-regulated, whereas PGE2 synthase (PGES) and PGE2 are up-regulated. Murine carcinogenesis models of human lung cancer reciprocate the relationship between PGIS and PGES expression. PGIS-overexpressing transgenic mice are protected from carcinogen-and tobacco smoke -induced lung tumor formation, suggesting that PGI2 may play a role in chemoprevention. We investigated several potential mechanisms for the down-regulation of PGIS in human lung cancer. Using transcription reporter assays, we show that single nucleotide polymorphisms in the PGIS promoter can affect transcriptional activity. In addition, PGIS expression in several human lung cancer cell lines is silenced by CpG methylation, and we have mapped these sites across the variable number of tandem repeats (VNTR) sequence in the promoter, as well as CpGs within exon 1 and the first intron. Finally, using fluorescence in situ hybridization, we show that human lung cancer cell lines and lung cancer tissues do not have a loss of the PGIS genomic region but multiple copies. These results show that an individual's PGIS promoter haplotype can play an important role in the predisposition for lung cancer and CpG methylation provides an epigenetic mechanism for the down-regulated PGIS expression. (Mol Cancer Res 2007;5(3):295 -308)

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Section: Introductionsupporting

confidence: 55%

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Stearman

Grady

Nana‐Sinkam

et al. 2007

Molecular Cancer Research

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“…The importance of the first objective relates to our observation that structurally distinct COX-2 inhibitors depress PGI 2 biosynthesis by approximately 60% in healthy individuals (25,26). PGI 2 inhibits vascular smoothmuscle cell proliferation, platelet activation, and leukocyteendothelial cell interactions in vitro (38)(39)(40), and overexpression of PGI 2 synthase reduces blood pressure in pulmonary hypertension and the response to carotid injury in rodents (41,42). Recently, we reported that deletion of the PGI 2 receptor (IP) accelerates atherogenesis in LDLR-KO mice.…”

Section: Discussionmentioning

confidence: 99%

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

Praticò

Cyrus²,

Zhang³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

206

150

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The cyclooxygenase (COX) product, prostacyclin (PGI2), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI 2 biosynthesis substantially in humans. Because deletion of the PGI 2 receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF 1␣ by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI 2 biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 ؎ 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and͞or aspirin on plaque progression in humans is timely. P latelet-dependent vascular occlusion complicating fracture of an atherosclerotic plaque is thought to be the pathophysiological basis of both acute myocardial infarction and the majority of cases of stroke (1, 2). The efficacy of plateletinhibitory drugs-aspirin (3-5), clopidogrel (6), and dipyridamole (7)-in the secondary prevention of coronary and cerebrovascular disease has been established in randomized controlled clinical trials. Much less is known about the potential contribution of platelet activation to development and progression of the underlying atherosclerotic disease. Although platelets release mitogenic growth factors and bioactive lipids when activated (8, 9), their relative absence in the descriptive morphology of atherosclerotic lesions in humans has led to a reduction in emphasis on their role in pathogenesis (10). Therefore, such studies do not address the possibility that platelets activated in the circulation of patients with atherosclerosis (11) might release products that modulate lesion progression, and controlled clinical trials of antiplatelet agents on plaque progression have not been performed. Similarly, mouse models of atherosclerosis seem quite resistant to spontaneous thrombosis (12), and it is unknown whether their development of vascular lesions alone results in platelet ac...

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“…Prostacyclin overexpression protects mice from chronic hypoxia-induced PH. 23 Furthermore, prostacyclin receptor-deficient mice develop severe pulmonary hypertensive changes in response to chronic hypoxia. 24 A decrease in prostacyclin synthase expression has been noted in pulmonary arteries of patients with severe idiopathic PAH, portopulmonary hypertension, and HIV-associated PAH, 25 and urinary levels of prostacyclin metabolites are decreased in patients with PH.…”

Section: Prostacyclinmentioning

confidence: 99%

Endothelial Dysfunction in Pulmonary Hypertension

2004

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

Cited by 205 publications

References 29 publications

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Genetic and Epigenetic Regulation of the Human Prostacyclin Synthase Promoter in Lung Cancer Cell Lines

Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

Endothelial Dysfunction in Pulmonary Hypertension

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