Background-Cardiovascular side effects associated with cyclo-oxygenase-2 inhibitor drugsdominate clinical concern. Cyclo-oxygeanse-2 is expressed in the renal medulla where inhibitioncauses fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygeanse-2 inhibition and cardiovascular events are unknown and no biomarkers have beenidentified.Methods and Results-Transcriptome analysis of wild-type and cyclo-oxygenase-2-/- mousetissues revealed 1 gene altered in heart and aorta but >1000 genes in the renal medulla includingthose regulating the endogenous NO synthase inhibitors ADMA and L-NMMA; Cyclooxygeanse-2-/- mice had increased plasma levels of ADMA and L-NMMA and reducedendothelial NO responses. These genes and methylarginines were not similarly altered in micelacking IP-/-). Wild-type mice or human volunteers taking cyclooxygeanse-2 inhibitors also showed increased plasma ADMA. Endothelial NO is cardioprotective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA isassociated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker andmechanistic bridge between renal cyclo-oxygenase-2 inhibition and systemic vasculardysfunction with non-steroidal anti-inflammatory drug usage.Conclusions-We identify the endogenous eNOS inhibitor ADMA as a biomarker andmechanistic bridge between renal COX-2 inhibition and systemic vascular dysfunction.
Ahmetaj-Shala, B., Kirkby, N. S., Knowles, R., Al’Yamani, M., Mazi, S., Wang, Z., Tucker, A. T., Mackenzie, L., Armstrong, P. C. J., & Nusing, R. M. (2014). Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs. Circulation, 131(7), 633-642. https://doi.org/10.1161/CIRCULATIONAHA.114.011591