ROLE OF CYCLOOXYGENASE-2 PATHWAY IN ANTI-OXIDATIVE EFFECT OF ASPIRIN AND IN ANGIOTENSIN II-INDUCED OXIDATIVE STRESS: PP.29.160

Abstract

Objective: Cyclo-oxygenase (COX)-2 overreaction is implicated in numerous human diseases and could elicit inflammation and free radicals generation. Angiotensin II (AngII) stimulates COX-2 expression and induces oxidative stress in cardiovascular tissues. Aspirin reduces superoxide (O2-) production and prevents AngII-induced oxidative stress and hypertension. The present study was designed to evaluate the role of the COX-2 pathway in the antioxidative effect of aspirin. Methods: The COX-1 (COX-1-/-) or COX-2 (COX-2-/-) knock-out mice and the cultured aortic smooth muscle cells (SMCs) from these animals were treated either with aspirin or AngII for 14 days (in vivo) or for 48 hours (cell culture). The O2- production was measured with the lucigenin-enhanced chemiluminescence method. Results: In vivo study. As observed on wild type mice, aspirin treatment reduced and AngII treatment increased the cardiovascular tissue O2- production in COX-1-/- mice. AngII treatment also significantly increased the blood pressure in those mice. At variance from wild type or COX-1-/- mice, AngII treatment increased only moderately the O2- production and blood pressure in COX-2-/- mice. Histological analysis showed the presence of hypertrophy on renal arterioles in untreated COX-2-/- mice and in AngII-treated wild type or COX-1-/- mice. Study on cultured SMC. Aspirin treatment reduced the AngII-enhanced O2- production on cultured aortic SMCs from wild type mice by 23% and COX-1-/- mice by 30%. The basal O2- level produced by SMCs from COX-2-/- mice was significantly lower than that from wild type or COX-1-/- mice. AngII infusion brought the O2¡¥B production rate back to the basal level of WT mice. Aspirin treatment neither reduced the basal O2- level nor inhibited the AngII-enhanced O2- production on cultured SMCs from COX-2-/- mice. Conclusions: a) The COX-2 pathway plays an important role in the redox balance in cardiovascular tissue. b) The COX-2 pathway appears to be responsible in great part for the antioxidative and cardiovascular protective effect of aspirin against AngII.