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

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        Author
        Ahmetaj-Shala, Blerina
        Kirkby, Nicholas S.
        Knowles, Rebecca
        Al'Yamani, Malak
        Mazi, Sarah
        Wang, Zhen
        Tucker, Arthur T.
        Mackenzie, Louise
        Armstrong, Paul C. J.
        Nüsing, Rolf M.
        Tomlinson, James A. P.
        Warner, Timothy D.
        Leiper, James
        Mitchell, Jane A.
        Attention
        2299/15823
        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.
        Publication date
        2015-02-17
        Published in
        Circulation
        Published version
        https://doi.org/10.1161/CIRCULATIONAHA.114.011591
        License
        http://creativecommons.org/licenses/by/4.0/
        Other links
        http://hdl.handle.net/2299/15823
        Relations
        School of Life and Medical Sciences
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