Disease relevance of PTGIS

• PTGIS promoter was hypermethylated in 43 out of 100 colorectal cancers and in all cell lines [1].
• A stepwise forward selection procedure demonstrated that ITGA2, GCK, and PTGIS genotypes significantly affected the prevalence of hypertension [2].
• Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer [3].
• Immunohistochemical distribution of renal prostaglandin endoperoxide synthase and prostacyclin synthase: diminished endoperoxide synthase in the hepatorenal syndrome [4].
• As in human ankylosing spondylitis, the MHC was the major permissive genetic locus in murine PG-induced spondylitis (PGIS) [5].

High impact information on PTGIS

• Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation [6].
• Selective augmentation of prostacyclin production by combined prostacyclin synthase and cyclooxygenase-1 gene transfer [7].
• Combined COX-1 and PGIS gene transfer has the potential for therapeutic augmentation of prostacyclin [7].
• Next, we determined the optimal ratio of Ad-COX-1 to Ad-PGIS by transfecting human umbilical vein endothelial cells with various titers of these 2 adenoviral constructs and determined the level of protein expression and prostanoid synthesis [7].
• Our results show that optimal ratios of adenoviral titers to achieve a large prostacyclin augmentation without overproduction of prostaglandin E2 or F2alpha were 50 to 100 plaque forming units (pfu) of Ad-COX-1 to 50 pfu of Ad-PGIS per cell [7].

Chemical compound and disease context of PTGIS

• Increased pulmonary production of prostaglandin I2 (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models [8].
• To evaluate possible causes of the diminished prostaglandin production in advanced hepatorenal syndrome, prostaglandin endoperoxide synthase and prostacyclin synthase were localized and semiquantitated by immunofluorescence in postmortem, biopsy and nephrectomy renal tissues [4].
• The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of thromboxane A2 (TXA2) and of lipoxygenase-derived products with the ability to inhibit prostacyclin synthase [9].
• Bolus methylprednisolone therapy or cytomegalovirus infection did not show any link with PTGIP [10].

Biological context of PTGIS

• PTGIS hypermethylation was associated with aneuploidy and p53 mutations [1].
• Hypermethylation of the PTGIS promoter was associated with diminished gene expression, that was restored after treatment with demethylating and histone deacetylases inhibitor agents [1].
• Cyclic mechanical stretch augments prostacyclin production in cultured human uterine myometrial cells from pregnant women: possible involvement of up-regulation of prostacyclin synthase expression [11].
• The data indicate, first, that the developing placenta contains PGI synthase, but in amounts which are relatively small and do not appear to increase with advancing gestation [12].
• Not prostacyclin synthase but prostaglandin endoperoxide synthase increases with human placental development [12].

Anatomical context of PTGIS

• Immunohistochemistry confirmed the expression of PGIS by luminal epithelia, tubal smooth muscle, vascular endothelial cells, and vascular smooth muscle cells [13].
• Thus, the fallopian tube expresses both COX isoforms and PGIS [13].
• Double-label expression studies of prostacyclin synthase, thromboxane synthase and COX isoforms in normal aortic endothelium [14].
• Differential expression and regulation of cylooxygenases, prostaglandin E synthases and prostacyclin synthase in rat uterus during the peri-implantation period [15].
• These results are in contrast to the extensive co-localization of PGIS and COX-2 in bronchiolar epithelium [14].

Associations of PTGIS with chemical compounds

• Bisulfite sequencing and clonal analysis confirmed the results obtained by AIMS and demonstrated biallelic hypermethylation of PTGIS promoter [1].
• Homolytic fission of the O-O bond of peroxynitrite yields NO2. and HO.. The fact that 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), which reacts with NO. to form NO2., dramatically potentiated the IL-1beta effect suggests that NO2. could be a species implicated in the inactivation of PGIS [16].
• The NO synthase inhibitor NG-monomethyl-L-arginine also antagonized the PGIS inhibitory effect of IL-1beta, indicating that NO. was also involved [16].
• NO. reacts with O2-. to form peroxynitrite, which has been reported to inactivate PGIS [16].
• The involvement of HO. in the PGIS inactivation was supported by the fact that deferoxamine, pyrrolidinedithiocarbamate, DMSO, mannitol, and captopril antagonized the effect of IL-1beta on PGIS to different degrees [16].

Regulatory relationships of PTGIS

• 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 [17].
• Here, we report that intracellular prostacyclin formed by expressing prostacyclin synthase in human embryonic kidney 293 cells promotes apoptosis by activating endogenous peroxisome proliferator-activated receptor delta (PPAR delta) [18].

Other interactions of PTGIS

• Western blot analysis revealed the expression of PGI synthase (PGIS) and PGI receptor by fallopian tubes [13].
• PGIS and PGHS-2 were also colocalized to ER in serum-treated or adenovirus-cyclooxygenase-2-infected cells [19].
• Western blot analyses revealed a predominant protein band of 180 kDa, and a second 16-kDa band for ir-PGES and 56-kDa band for ir-PGIS [20].
• We investigated several potential mechanisms for the down-regulation of PGIS in human lung cancer [17].
• Our results also underline the importance of PTGIS and PPARD in the trophoblast and PTGIR in the uterus, suggesting that PGI2 is of both uterine and trophoblastic origin and is involved in a complex signalling pathway at around the time of implantation in the ewe [21].

Analytical, diagnostic and therapeutic context of PTGIS

• In rat and human aortas, immunofluorescence studies also showed significant COX-1 and PGIS co-localization in the endothelium [14].
• 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 [17].
• PGIS-overexpressing transgenic mice are protected from carcinogen- and tobacco smoke-induced lung tumor formation, suggesting that PGI2 may play a role in chemoprevention [17].
• Genomic Southern blot and fluorescence in situ hybridization analyses revealed that the human prostacyclin synthase gene is present as a single copy per haploid genome and is localized on chromosome 20q13 [22].
• In a Minnesota-based case-control study of adenomatous (n = 517) or hyperplastic (n = 192) polyps versus polyp-free controls (n = 618), we investigated the role of promoter repeat polymorphisms in PGIS and ALOX5 as well as ALOX5 -1700 G>A [23].

References