Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine

C yclooxygenase (COX) catalyzes the conversion of ara-chidonic acid to prostaglandin H 2 , which is then further metabolized by downstream synthase enzymes to a range of eicosanoids. COX is expressed in 2 isoforms, constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflamma-tory drugs (NSAIDs) are widely used to treat inflammation and pain and show potential to prevent cancer. COX-2 is the therapeutic target of NSAIDs, although most members of this class of drugs inhibit both isoforms of COX 1 and, as a consequence, are associated with gastrointestinal side effects. 2 NSAID-induced gastrointestinal side effects are relatively common and can be serious, limiting the use of these drugs in some patients and proving fatal in others. 3 COX-2 selective inhibitors such as Vioxx (rofecoxib) and Celebrex Background—Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified. Methods and Results—Transcriptome analysis of wild-type and cyclooxygenase-2 –/– mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2 –/– mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage. Conclusions—We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction. (celecoxib) were originally developed to target COX-2 at the site of inflammation while sparing COX-1 in the gut and so reducing the gastrointestinal side effects typical of NSAIDs. 4 However, now, cardiovascular side effects associated with COX-2 inhibition dominate concern over NSAID usage 5–7 and have stopped the development of new drugs in this class. The cardiovascular side effects caused by the inhibition of COX-2 are mainly myocardial infarctions, 8,9 which implies increased thrombosis and atherosclerosis and have been considered to reflect …