Evidence That Links Loss of Cyclooxygenase-2 With Increased Asymmetric Dimethylarginine: Novel Explanation of Cardiovascular Side Effects Associated With Anti-Inflammatory Drugs

Blerina Ahmetaj-Shala, Nicholas S. Kirkby, Rebecca Knowles, Malak Al’Yamani, Sara Mazi, Zhen Wang, Arthur T. Tucker, Louise Mackenzie, Paul C.J. Armstrong, Rolf M. Nusing, James A. P. Tomlinson, Timothy D. Warner, James Leiper, Jane A. Mitchell

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)633-642
Number of pages10
JournalCirculation
Volume131
Issue number7
DOIs
Publication statusPublished - 9 Dec 2014

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