Cyclooxygenase-2 and inflammation in atherosclerosis

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Abstract

By regulating the production of eicosanoids, cyclooxygenase (COX) modulates processes contributing to atherosclerosis and thrombosis, including platelet aggregation and the local inflammatory response. COX-2, a key mediator of inflammation, is upregulated in activated monocyte/macrophages, suggesting that COX-2 inhibition might reduce atherogenesis through its anti-inflammatory effects. In mouse models, selective inhibition of COX-2 or its deletion in macrophages protects against early atherosclerosis. The discovery that macrophage COX-2 is downregulated by oxidized low-density lipoprotein and liver X receptors indicates coordinated and reciprocal control of cholesterol homeostasis and inflammatory pathways. Thus, the impact of macrophage COX-2 expression on atherogenesis might be attenuated in advanced lesions. Concerns have been raised that inhibition of COX-2 might promote thrombotic cardiovascular events by disturbing the balance between platelet thromboxane A2 and endothelial prostacyclin. However, meta-analyses of randomized trials have failed to show excess of cardiovascular events among patients on COX-2 inhibitors. Prospective randomized evaluation of the effects of selective COX-2 inhibitors on cardiovascular events is warranted.

Section snippets

Introduction: cyclooxygenase and atherosclerosis

Atherosclerosis is viewed as an inflammatory disease [1]. Eicosanoids play a central role in inflammation and have been implicated in the pathogenesis of atherosclerosis and thrombosis 2., 3.. Cyclooxygenase (COX), or prostaglandin (PG)H2 synthase, catalyses the first committed step in the biosynthesis of PGs by converting arachidonic acid to PGH2 [3]. PGH2 is rapidly converted into several different eicosanoids, including PGE2, PGD2, PGF2α, PGI2 and thromboxane (TX)A2 [2]. COX exists in two

Non-selective inhibition of cyclooxygenase and atherosclerosis

The beneficial effects of low-dose aspirin in the secondary prevention of cardiovascular events are believed to be caused by inhibition of TXA2 production by platelets, with a consequent reduction in platelet aggregation 37., 38., 39.. The observation that aspirin reduces myocardial infarction rates in men with high levels of C-reactive protein in plasma [40] suggests that some of the beneficial effects of aspirin on coronary events may stem from its anti-inflammatory effects. Non-steroidal

Cyclooxygenase-2 expression in atherosclerotic lesions

Reports demonstrating the presence of COX-2 expression by monocyte/macrophages, endothelial cells and smooth muscle cells in human atherosclerotic lesions 25., 44. suggested a possible role for COX-2 expression in promoting the inflammatory process of atherogenesis. COX-1 is expressed abundantly in normal arteries and in atherosclerotic lesions, whereas COX-2 expression is restricted to atherosclerotic lesions and is not seen in normal arteries 25., 44.. Recently, we examined the distribution

Selective inhibition of cyclooxygenase-2 and atherosclerosis

A number of studies examining the impact of selective COX-2 inhibition on the development of atherosclerosis in murine models have been reported over the past three years. The results have been mixed: treatment with selective COX-2 inhibitors has been reported to decrease, increase or have no impact on atherosclerosis 42., 43.•, 60., 61., 62.•. Taken at face value, these studies suggest that the role of COX-2 in atherosclerosis is complex and may vary with lesion stage or animal model. However,

Genetic deletion of macrophage cyclooxygenase-2

Another possible explanation for the disparate effects of different COX-2 inhibitors on the development of atherosclerosis in murine models is that the various agents used might have unanticipated effects on other targets. This explanation needs to be considered because indomethacin and several other NSAIDs have been reported to bind to PPARs [71]. Therefore, we used a genetic approach to further examine the role of COX-2 in atherogenesis by means of fetal liver cell transplantation 43.•, 72.,

COX-2 inhibitors and cardiovascular events

Concerns have been raised that treatment with selective COX-2 inhibitors might increase cardiovascular events, largely because the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial showed an increase in myocardial infarction rate in rheumatoid arthritis patients treated with rofecoxib (50 mg/d) versus naproxen [74]. Aspirin use was not permitted in VIGOR, and the results of this study could reflect a reduced incidence of myocardial infarction in the naproxen group owing to the efficacy of

Conclusions

The inflammatory aspects of atherosclerosis include the COX-dependent prostaglandin cascade. Activation of this pathway in arterial macrophages precedes, and could affect, their transformation into foam cells. The discovery that COX-2 is downregulated by LXRs indicates coordinated and reciprocal control of cholesterol homeostasis and inflammatory pathways, including PG production in macrophages. A sequence can be envisioned where cholesterol accumulation in the macrophage leads to oxysterol

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

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    of special interest

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    of outstanding interest

Acknowledgements

The authors are supported by National Institutes of Health grants HL53989, HL58427, HL57986 and HL65405.

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