Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs

Ahmetaj-Shala, B. et al. (2015) 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), pp. 633-642. (doi: 10.1161/CIRCULATIONAHA.114.011591) (PMID:25492024) (PMCID:PMC4768634)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leiper, Professor James
• Authors: 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., Tomlinson, J. A.P., Warner, T. D., Leiper, J., and Mitchell, J. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Circulation
• Publisher: American Heart Association
• ISSN: 0009-7322
• ISSN (Online): 1524-4539
• Published Online: 09 December 2014
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Circulation 131(7):633-642
• Publisher Policy: Reproduced under a Creative Commons License