Cyclooxygenase-2 Induction in Congestive Heart Failure

yclooxygenase-2, like the other member of the COX family, COX-1, is a bifunctional enzyme that catalyzes the conversion of arachidonic acid to PGG 2 via COX activity and PGG 2 to PGH 2 via peroxidase activity.PGH 2 is the precursor for PGs, prostacyclin, and TXA 2 .Hence, COX-2 occupies a central position in the biosynthesis of proinflammatory PGE 2 and vasoactive prostacyclin and TXA 2 .COX-2 shares with COX-1 most of its catalytic and structural properties.The crystallographic structure of COX-2 reveals a branched substrate channel, as contrasted to a nonbranched, more rigid COX-1 channel structure.1,2 This difference in substrate channel structure forms the basis for selective inhibition of COX-2 by newly developed compounds containing a side chain that snugly fits the substrate channel of COX-2 but not COX-1.3 COX-2 is encoded by a gene Ϸ8 kb in size located on the long arm of chromosome 1 (q25.2-q25.3).4,5 The COX-1 gene, on the other hand, is Ϸ22 kb and is located on chromosome arm 9q32-q33.3.5,6 In contrast to COX-1, which is constitutively expressed in most tissues, COX-2 expression is induced in inflammatory cells by a variety of agents, including cytokines, mitogenic factors, PGs, and hypoxia.7 These agents induce COX-2 transcription by involving different regulatory elements and putative binding sites on the 5Ј-flanking untranslated region of the COX-2 gene.4 It has been shown in murine 3T3 cells that COX-2 induction by v-src, platelet-derived growth factor, or serum is mediated by the cAMP response element at Ϫ59 to Ϫ53. 8,9 COX-2 induction in bovine endothelial cells by phorbol 12-myristate 13-acetate involves both the cAMP response element and the NF-IL-6 site (Ϫ132 to Ϫ124). 10 Induction of COX-2 by tumor necrosis factor-␣ in a murine osteoblastic cell line, the MC 3T3-E1 cell, requires both the NF-IL-6 site and an NF-B site at Ϫ401 to Ϫ393.11 In the human COX-2 promoter, there is an additional NF-B site at a more proximal region (Ϫ213 to Ϫ222). 4 Preliminary data from our laboratory indicate that this site is required for IL-1-mediated COX-2 induction in cultured human dermal fibroblasts and umbilical vein endothelial cells.