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

Research output: Contribution to journalArticle

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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