The prostanoids are a family of lipid mediators generated by the action of cyclooxygenase on a 20-carbon unsaturated fatty acid, arachidonic acid. Prostanoids are generated widely in response to diverse stimuli and, acting in a paracrine or autocrine manner, play important roles in normal physiology and disease. This review summarizes the current knowledge on prostanoid generation and the roles of individual mediators, their biosynthetic pathways, and their receptors in health and disease. Arachidonic acid (AA), a 20-carbon unsaturated fatty acid, is the predominant precursor for a family of lipid mediators, the eicosanoids. Eicosanoid biosynthesis begins with release of AA, esterified in the sn-2 domain of membrane phospholipids, by the action of phospholipase A 2 , particularly group IVA cytosolic cPLA 2 . Three major groups of enzymes, prostaglandin G/H synthases, lipoxygenases, or epoxygenases, then catalyze the formation of the prostaglandins (PGs) and thromboxane A 2 (TxA 2 ), the leukotrienes, or the epoxyeicosatrienoic acids, respectively. A parallel family of free radical catalyzed isomers, the isoeicosanoids, is formed by nonenzymatic peroxidation of AA in situ (1). This review will focus on the PGs and TxA 2 , collectively termed the prostanoids (Fig. 1), in normal physiology and disease. PROSTANOID BIOSYNTHESISProstanoids are formed by the action of prostaglandin G/H synthase, or cyclooxygenase (COX), on AA. COX, an evolutionarily conserved (2) bisfunctional enzyme, exists as two distinct isoforms, COX-1 or COX-2. COX-1, expressed constitutively in most cells, is the dominant (but not exclusive) source of prostanoids for housekeeping functions, such as gastric epithelial cytoprotection and hemostasis. COX-2, induced by cytokines, shear stress, and tumor promoters, is the more important source of prostanoid formation in inflammation and perhaps cancer. However, both enzymes contribute to the generation of autoregulatory and homeostatic prostanoids, and both can contribute to prostanoid formation during inflammation.COX-1 or COX-2 function as homodimers, and perhaps heterodimers (3), inserted into the endoplasmic reticular membrane, to transform AA into the unstable cyclic endoperoxides PGG 2 and PGH 2 (Fig. 1). Downstream isomerases and synthases complete the biosynthesis of TxA 2 and D, E, F, and I series PGs. COX-1 and COX-2 are closely related in their amino acid sequence and crystal structure (4). Isoformspecific preference for downstream enzymes has been reported in heterologous expression systems, although the biological relevance is unknown. COX-1 couples preferentially, but not exclusively, with thromboxane synthase, prostaglandin F synthase, and the cytosolic prostaglandin E synthase (PGES) isozymes. COX-2 prefers prostaglandin I synthase (PGIS) and the microsomal (m) PGES isozymes, both of which are induced by cytokines and tumor promoters. Two forms of prostaglandin D and F synthase have been identified, underscoring the diversity of the isomerases and synthases. PROSTANOID RECEPTO...

Dietary fish oil containing 3 highly unsaturated fatty acids has cardioprotective and anti-inflammatory effects. Prostaglandins (PGs) and thromboxanes are produced in vivo both from the 6 fatty acid arachidonic acid (AA) and the 3 fatty acid eicosapentaenoic acid (EPA). Certain beneficial effects of fish oil

Female gender affords relative protection from cardiovascular disease until the menopause. We report that estrogen acts on estrogen receptor subtype alpha to up-regulate the production of atheroprotective prostacyclin, PGI2, by activation of cyclooxygenase 2 (COX-2). This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the PGI2 receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. This suggests that chronic treatment of patients with selective inhibitors of COX-2 could undermine protection from cardiovascular disease in premenopausal females.