Abstract 697: Cyclooxygenase 2-Selective and Non-Selective Non-Steroidal Anti-Inflammatory Drugs Induce Oxidative Stress by Upregulating Vascular NADPH oxidases
Clinical studies have indicated that cyclooxygenase 2 (COX2)-selective inhibitors (coxibs) are associated with an increase in cardiovascular events. This phenomenon has been explained by an imbalance between prostacyclin and thromboxane, because a significant part of endothelial prostacyclin synthesis depends on COX2, whereas platelet thromboxane is synthesized solely via the COX1 pathway. However, the above hypothesis has to be questioned, as recent clinical studies with non-selective non-steroidal anti-inflammatory drugs (NSAIDs) have indicated that also this class of drugs increases the risk of cardiovascular disease. Therefore, other pathogenic mechanisms have to be postulated. The present study puts forth a novel theory that can explain the adverse cardiovascular effects of both coxibs and non-selective NSAIDs. Spontaneously hypertensive rats (SHR) were treated for two weeks with rofecoxib (10 mg/kg/d), celecoxib (30 mg/kg/d), diclofenac (5 mg/kg/d) or naproxen (50 mg/kg/d). In aorta and heart, mRNA expression of the NADPH oxidase subunits p22phox and gp91phox (Nox2), and the gp91phox homologues Nox1 and Nox4 were markedly increased by the non-selective NSAIDs diclofenac and naproxen, and moderately by rofecoxib or celecoxib. The upregulation of NADPH oxidases by NSAIDs was associated with increased superoxide production in aorta and heart and increased lipid peroxides in plasma. In parallel, NSAIDs reduced plasma nitrite (indicating reduced vascular NO production) and diminished the phosphorylation of vasodilator-stimulated phosphoprotein (VASP, indicating reduced functionality of the NO/cGMP/cGK pathway). Also in human endothelial cells, NSAIDs diminished bioactive NO, and NSAID treatment of healthy volunteers reduced nitroglycerin-induced NO-mediated vasodilatation of the brachial artery. These results indicate that NSAIDs may increase cardiovascular risk by inducing oxidative stress in the vasculature, with non-selective NSAIDs (particularly diclofenac) being more critical than coxibs.