Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice

The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Bio chemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substa ntially in humans. Because deletion of the PGI(2) receptor accelerates athe rogenesis in the fat-fed low density lipoprotein receptor knockout mouse, w e wished to determine whether selective inhibition of COX-2 would accelerat e atherogenesis in this model. To address this hypothesis, we used dosing w ith nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 diner 6-keto PGF(1 alpha) by approximately 60% but had no effect on thromboxane f ormation by platelets, which only express COX-1. By contrast, the isoform n onspecific inhibitor, indomethacin, suppressed platelet function and thromb oxane formation ex vivo and in vivo, coincident with effects on PGI(2) bios ynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, b oth drugs depressed two indices of systemic inflammation, soluble intracell ular adhesion molecule-1, and monocyte chemoattractant protein-1 to a simil ar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis, Accelerated progression of atherosclerosis is unlikely during chronic intake of specifi c COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids co ntribute to atherogenesis suggests that controlled evaluation of the effect s of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progress ion in humans is timely.