Functional promoter polymorphism of cyclooxygenase‑2 modulates the inflammatory response in stable coronary heart disease

INTRODUCTION: 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. OBJECTIVES: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.