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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 11, 2008; DOI: 10.1124/jpet.108.139030

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Received for publication March 14, 2008.
Revised June 4, 2008.
Accepted for publication June 5, 2008.

COX2-selective and non-selective NSAIDs induce oxidative stress by upregulating vascular NADPH oxidases

Huige Li 1, Marcus Hortmann 1, Andreas Daiber 1, Matthias Oelze 1, Mir Abolfazl Ostad 1, Petra M Schwarz 1, Hui Xu 1, Ning Xia 1, Andrei L Kleschyov 1, Christian Mang 1, Ascan Warnholtz 1, Thomas Munzel 1, Ulrich Forstermann 1*

1 Johannes Gutenberg University of Mainz

* Address correspondence to: E-mail: ulrich.forstermann{at}uni-mainz.de

Abstract

Cyclooxygenase 2 (COX2)-selective inhibitors (coxibs) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increase in cardiovascular events. The current study was designed to test the effect of coxibs and non-selective NSAIDs on vascular superoxide and NO production. mRNA expression of endothelial NO-synthase (eNOS) and of the vascular NADPH oxidases was studied in spontaneously hypertensive rats (SHR) and in human endothelial cells. The expression of Nox1, Nox2, Nox4 and p22phox was increased markedly by the non-selective NSAIDs diclofenac or naproxen, and moderately by rofecoxib or celecoxib in the aorta and heart of SHR. The upregulation of NADPH oxidases by NSAIDs was associated with increased superoxide content in aorta and heart, which could be prevented by the NADPH oxidase inhibitor apocynin. NSAIDs reduced plasma nitrite and diminished the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). This demonstrates a reduction in vascular NO production. Aortas from diclofenac-treated SHR showed an enhanced protein nitrotyrosine accumulation, indicative of vascular peroxynitrite formation. Peroxynitrite can uncouple oxygen reduction from NO synthesis in eNOS. Accordingly, the eNOS inhibitor NG-nitro-L-arginine methyl ester reduced superoxide content in aortas of NSAID-treated animals, demonstrating eNOS uncoupling under those conditions. Also in human endothelial cells, NSAIDs increased Nox2 expression and diminished production of bioactive NO. In healthy volunteers, NSAID treatment 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 being even more critical than coxibs in this respect.


Key words: NADPH oxidase, cardiovascular diseases, drugs, endothelium-derived factors, free radicals, risk factors




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