Cyclooxygenase-2 Inhibition Limits Angiotensin II-Induced DNA Oxidation and Protein Nitration in Humans

Abstract

Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8-hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (-20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II-mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug.

Keywords: blood pressure; celecoxib; cycloxygenase-2 inhibition; endothelin-1; humans; nitric oxide; oxidative stress; renin-angiotensin system.

Figure 1

Plasma oxidative stress (8-OHdG) at baseline and in response to Angiotensin II infusion, pre- and post COX-2 inhibition. ^*p < 0.05 compared to corresponding baseline value. ^†p < 0.05 vs. corresponding timepoint pre-COX-2 inhibition.

Figure 2

Plasma endothelin-1 at baseline and in response to Angiotensin II infusion, pre- and post-COX-2 inhibition. ^*p < 0.05 compared to corresponding baseline value.