A Thousand Off-Target Effects of Targeted COX-2 Inhibitors

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ec2
DOI: 10.1126/scitranslmed.aaa3469

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by inhibiting cyclooxygenase (COX), although their use is limited by COX-1–mediated gastrointestinal side effects. COX-2 inhibitors were developed to circumvent these side effects but had complications. In one of the biggest controversies in pharmaceutical history, COX-2 inhibitors were found to double the risk of cardiovascular disease. Now, a study by Ahmetaj-Shala et al. points to kidney-generated inhibitors of nitric oxide synthase as a major culprit in these unwanted effects of COX-2 inhibition.

The group measured differential gene expression in wild-type and COX-2 deficient mice in a range of tissues (heart, aorta, blood, and kidney). Although none was altered in blood and only one in cardiovascular tissues, over 1000 genes were differentially expressed in the kidneys of COX-2-/- mice. Through pathway analysis of genes relevant to cardiovascular risk, the authors identified gene clusters related to turnover of methylarginines (ADMA and L-NMMA)—endogenous inhibitors of nitric oxide synthase. The circulating levels of these molecules increased in mice deficient in COX-2, with an associated reduction in vasomotor reactivity that could be reversed by L-arginine. Plasma ADMA rapidly rose in both mice and humans given oral COX-2 inhibitors to a concentration that is associated with cardiovascular risk in man, suggesting clinical relevance.

In light of these new findings, prevailing ideas that COX-2’s dangerous cardiovascular effects result from direct effects on blood vessels may need revision. Instead, they argue for a role of kidney-derived methylarginines acting on the cardiovascular system as circulating hormones. ADMA might serve as a risk biomarker and L-arginine as a potential therapy, reopening the possibilities of safe COX-2 inhibitor use.

B. Ahmetaj-Shala et al., Evidence that links loss of cyclo-oxygenase-2 with increased asymmetric dimethylarginine: Novel explanation of cardiovascular side effects associated with anti-inflammatory drugs. Circulation 10.1161/CIRCULATIONAHA.114.011591 (2014). [Abstract]

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