EP Receptors and Coxibs

Few chemical compounds have demonstrated a controversial association with a specific disease such as arachidonic acid with atherothrombosis. Arachidonic acid metabolism is deeply linked to atherothrombosis because compounds generated by this cascade, the eicosanoids, are key regulators of several pathophysiological processes critically involved in vessel homeostasis and blood clotting. After its release from membrane-bound phospholipids, arachidonic acid is metabolized by 4 main pathways: (1) prostaglandin (PG) endoperoxidase synthase, usually referred as cyclooxygenase (COX); (2) lipoxygenase; (3) P450 epoxygenase; and (4) nonenzymatic isoprostane biosynthesis1 (Figure 1). Among these pathways, cardiovascular research has mainly focused on COX-derived eicosanoids, usually called PGs. There are 2 main isoforms of COX, named COX-1 and COX-2, which are encoded by 2 separate genes. Whereas COX-1 is constitutively expressed in many tissues, the expression of COX-2 is induced by several proinflammatory cytokines and growth factors. In the vascular tree, COX-1 is expressed in endothelial cells and in vascular smooth muscle cells (VSMCs) both in healthy vessels and in atheromatous areas. On the contrary, COX-2 expression is evident in atherosclerotic regions, and several proatherosclerotic stimuli (ie, oxidized low-density lipoprotein, angiotensin II, advanced glycation elements)2 as well as vascular injury3 may increase its expression. Notably, COX-2 is highly expressed in macrophages located in the shoulder region of atherosclerotic plaques, both in mice4 and in humans.5 In macrophages, the expression of COX-2 has predominantly proinflammatory and proatherosclerotic effects, and selective deletion of COX-2 in macrophages significantly hampers the progression of atherosclerosis in mice.4,6Figure 1. The cyclooxygenases pathway. ECs indicates endothelial cells; EP, PGE2 receptor; DP, PGD2 receptor; FP, PGF2α receptor; IP, prostacyclin receptor; …