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The Cycloxygenase 2 (COX-2) Story: It's Time to Explain, Not Inflame

Division of Cardiology, University of Texas Medical Branch, Galveston, Texas

Umamahesh C. Rangasetty, MD

Division of Cardiology, University of Texas Medical Branch, Galveston, Texas

Barry F. Uretsky, MD

Division of Cardiology, University of Texas Medical Branch, Galveston, Texas

Yochai Birnbaum, MD

Division of Cardiology, University of Texas Medical Branch, Galveston, Texas, yobirnba{at}utmb.edu, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas

Despite initial promising reports that anti-inflammatory properties of cycloxygenase-2 (COX-2) inhibitors may confer anti-atherosclerosis effects and stabilize the atherosclerotic plaque, subsequent data from long-term clinical trials have shown that selective COX-2 inhibitors are associated with increased risk of cardiovascular events. The commonly cited explanation is that selective inhibition of COX-2 leads to depletion of prostacyclin, whereas the production of pro-thrombotic thromboxane by means of cycloxygenase-1 (COX-1) is unopposed. This hypothesis seems unlikely as the overall explanation, because low-dose aspirin does not decrease the increased risk associated with COX-2 inhibitors. Moreover, the risk associated with nonselective COX inhibitors may be similar to selective COX-2 inhibitors. Alternative hypotheses include (1) elevated blood pressure, (2) abnormal vascular remodeling, (3) inhibition of protective mechanisms against ischemia—reperfusion injury, and (4) inhibition of 15-epi-lipoxin production. Varying results in different experimental models may be related to the fact that COX-2 is involved in numerous cellular functions. Inhibiting COX-2 in inflammatory cells may have favorable effects, whereas in organs such as the heart and brain and/or blood vessels may have deleterious effects. Currently, the "selective COX-2 inhibitors" are not selective in the sense that they inhibit COX-2 in all tissues without predilection to inflammatory cells and, as a result, may summate to increase the risk of cardiovascular events.

Key Words: cycloxygenase-2 (COX-2) • nonsteroidal antiinflammatory drugs • inflammation • cardiovascular disease

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 12, No. 2, 98-111 (2007)
DOI: 10.1177/1074248407301172


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