Functional promoter polymorphism of cyclooxygenase-2 modulates the inflammatory response in stable coronary heart...

Inflammatory mediators, including prostanoids produced by inducible cyclooxygenase-2 (COX-2), play a significant role in the development of atherosclerosis. A regulatory region of COX-2 gene has a common -765G>C polymorphism. Functional effects of this polymorphism and its association with atherosclerosis phenotypes have not been fully understood.

The aim of the study was to evaluate the association between COX-2 -765G>C polymorphism and the inflammatory response in patients with stable CAD.

We studied systemic prostaglandin E2 (PGE2) metabolism, the levels of soluble CD163 (sCD163) in serum (a marker of monocyte/macrophage activation), and COX-2 -765G>C polymorphism in patients with stable CAD. We also tested the patients for functional effects of COX-2 -765G>C polymorphism using cell lines, using the constructs in which red fluorescent protein expression was controlled by a large segment of COX-2 regulatory region.

Patients with stable CAD carrying the variant allele -765C allele had increased urinary excretion of PGE2 metabolite and higher serum levels of sCD163 than patients carrying the -765G allele. In contrast to these clinical findings, in vitro functional studies demonstrated that the -765C variant allele was less responsive than -765G allele to a wide range of COX-2 inducers.

A substantial part of total PGE2 biosynthesis is contributed by activated monocytes/macrophages in stable CAD. The exact mechanism of activation of this pathway in CAD requires further research because of the conflicting results on COX-2 -765G>C polymorphism provided by clinical studies and in vitro functional studies.