Organization of the Human Prostacyclin Synthase Gene and Association Analysis of a Novel CA Repeat in Essential Hypertension

Abstract

In 1976, Vane et al discovered prostacyclin (PGI2) that is a potent inhibitor of platelet secretion and aggregation, smooth muscle cell proliferation and vasoconstriction^1–3. It is considered to play a key role in vasoprotection and its deficiency may lead to thrombosis and other vascular lesions^{4, 5}. Biosynthesis of PGI2 is catalyzed serially by phospholipase A2 which liberates arachidonic acid from the sn-2 position of membrane phospholipids, prostaglandin H2 synthase, a bifunctional enzyme which catalyzes the conversion of arachidonic acid to prostaglandin G2 and subsequently to prostaglandin H2, and prostacyclin synthase (PGIS, EC 5.3.99.4) which catalyzes the formation of PGI2 from prostaglandin H2. PGIS has been shown to be widely distributed, predominantly in vascular endothelial and smooth muscle cells^{6, 7}. The enzyme is a membrane-bound protein located in the endoplasmic reticulum. It exhibits spectral characteristics of cytochrome P450s but has no mono-oxygenase activity^{8, 9}. Instead, it catalyzes an isomerization reaction and thus does not require a reductase to initiate the catalytic activity. A description has been given of the cDNA of human PGIS¹⁰ and the deduced amino acid sequence. In the present study, the genomic organization of the human PGIS gene was investigated¹¹, and the association study of essential hypertension was carried out using a novel CA/TG dinucleotide repeat polymorphism in this gene¹².