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

• DOI: 10.1073/pnas.061607398
• Publication Date: 2002-07-26T14:41:48Z
• Authors: Domenico Praticò; Cyrus Tillmann; Zhi-Bing Zhang; Hongwei Li; Garret A. FitzGerald
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Sulfonamides; Cyclooxygenase 2 Inhibitors; Indomethacin; Membrane Proteins; 6-Ketoprostaglandin F1 alpha; Coronary Artery Disease; Epoprostenol; Isoenzymes; Mice, Inbred C57BL; Thromboxane B2; Mice; 03 medical and health sciences; Receptors, LDL; Cyclooxygenase 2; Prostaglandin-Endoperoxide Synthases; Cyclooxygenase 1; Animals; Cyclooxygenase Inhibitors; Female

The cyclooxygenase (COX) product, prostacyclin (PGI 2 ), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI 2 biosynthesis substantially in humans. Because deletion of the PGI 2 receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo , depressed urinary 2,3 dinor 6-keto PGF 1α by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo , coincident with effects on PGI 2 biosynthesis 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, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar 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 specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.