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

Abstract

The cyclooxygenase (COX) product, prostacyclin (PGI2), 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 1␣ 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 and͞or aspirin on plaque progression in humans is timely. P latelet-dependent vascular occlusion complicating fracture of an atherosclerotic plaque is thought to be the pathophysiological basis of both acute myocardial infarction and the majority of cases of stroke (1, 2). The efficacy of plateletinhibitory drugs-aspirin (3-5), clopidogrel (6), and dipyridamole (7)-in the secondary prevention of coronary and cerebrovascular disease has been established in randomized controlled clinical trials. Much less is known about the potential contribution of platelet activation to development and progression of the underlying atherosclerotic disease. Although platelets release mitogenic growth factors and bioactive lipids when activated (8, 9), their relative absence in the descriptive morphology of atherosclerotic lesions in humans has led to a reduction in emphasis on their role in pathogenesis (10). Therefore, such studies do not address the possibility that platelets activated in the circulation of patients with atherosclerosis (11) might release products that modulate lesion progression, and controlled clinical trials of antiplatelet agents on plaque progression have not been performed. Similarly, mouse models of atherosclerosis seem quite resistant to spontaneous thrombosis (12), and it is unknown whether their development of vascular lesions alone results in platelet ac...

Macrophages, inflammation, and atherosclerosis

“…Thus, our studies demonstrate a role for COX-2-dependent prostanoid formation in promoting atherogenesis. Consistent with our studies, Pratico et al 16 reported a trend for a reduction in atherosclerosis in LDL-deficient mice treated with nimesulide, and Krul et al 17 have recently presented data that treatment of apoE-deficient mice with a selective COX-2 inhibitor, celecoxib, results in a significant reduction in aortic atherosclerosis. Also, we generated LDLR À/À mice null for macrophage COX-2 by fetal liver cell transplantation to examine the role of macrophage COX-2 expression in atherosclerosis.…”

Modulation of COX-2 Expression by Statins in Human Aortic Smooth Muscle Cells

“…Although COX-2 expression is detected in atherosclerotic plaque where it is distributed in the intima and media (35) and urinary prostacyclin derivatives increased in patients with atherosclerotic plaques (36), the consequence of endothelial and smooth muscle cell increase in COX-2 expression is still a matter of debate. An increase in urinary prostacyclin derivatives has been shown recently in two murine models of atherosclerosis, ApoE-deficient mice and low-density lipoprotein receptor-deficient mice on a high fat diet (37,38). Selective inhibition of COX-2 failed to decrease the extent of atherosclerosis in these models suggesting that COX-2, although expressed in the atherosclerotic lesions, does not participate in its progression (38).…”

“…An increase in urinary prostacyclin derivatives has been shown recently in two murine models of atherosclerosis, ApoE-deficient mice and low-density lipoprotein receptor-deficient mice on a high fat diet (37,38). Selective inhibition of COX-2 failed to decrease the extent of atherosclerosis in these models suggesting that COX-2, although expressed in the atherosclerotic lesions, does not participate in its progression (38). Little is known about the roles of PGI 2 and PGE 2 on vessels.…”

Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation

“…Expression of human COX-2 is very specific in certain tissues at basal level, and it is widely expressed in human endothelium (40) and human brain (41). During its absorption and distribution, orally taken aspirin can interact and acetylate endothelial COX-2, blocking prostacyclin biosynthesis (42,43). Considering the large surface area of the human vasculature (~1,000 m 2 ; whole body estimate) (44), the EPA present in blood can be in contact with endothelial cells and converted to 18S-HEPE by acetylated COX-2 for further biosynthesis to 18S E-series resolvins via transcellular mechanisms with leukocytes (19,45).…”