Novel aspects of eicosanoid signaling through the use of gene-targeted mice

Abstract

Eicosanoids are lipid mediators consisting of prostaglandins, leukotrienes, lipoxins and related compounds derived primarily from arachidonic acid and to a lesser extent from eicosapentaenoic and di-homo-gammalinolenic acids. This large class of bioactive lipids is derived from the initial release of polyunsaturated fatty acid from the sn2 position of glycerophospholipids predominantly from cytosolic phospholipase A2 and subsequent conversion by either prostaglandin H synthases-1 and -2 (PGHS-1, PGHS-2; also known as COX- 1, COX-2), lipoxygenases or various members of the cytochrome P450 family. Eicosanoids control a vast array of physiological functions, including female reproductive function and parturition, platelet aggregation and vascular homeostasis, as well as renal function and roles in inflammation initiation and resolution. The authors have been studying the functions and signaling of eicosanoids, in particular the prostaglandin class of molecules, using a series of induced mutant mouse strains created in the laboratory by manipulation of the PGHS-1 and PGHS-2 genes by gene targeting in embryonic stem cells. The two strains of mice most fully characterized to date are referred to as ‘‘low-dose aspirin genetic mimic’’ or PGHS-1 knockdown and ‘‘selective COX-2 inhibitor genetic mimic’’ or PGHS-2 Y385F. This brief review describes the utility of these mouse models for unraveling new insights into eicosanoid signaling. Keywords: aspirin; cardiovascular; coxib; inflammation; prostaglandin