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@article{Kirkby:2020:cvr/cvz290,
author = {Kirkby, N and Raouf, J and Ahmetaj-Shala, B and Liu, B and Mazi, S and Edin, M and Geoffrey, Chambers M and Korotkova, M and Wang, X and Wahli, W and Zeldin, D and Nusing, R and Zhou, Y and Jakobsson, P-J and Mitchell, J},
doi = {cvr/cvz290},
journal = {Cardiovascular Research},
pages = {1972--1980},
title = {Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis},
url = {http://dx.doi.org/10.1093/cvr/cvz290},
volume = {116},
year = {2020}
}

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TY  - JOUR
AB  - Aims:Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of eNOS, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA.Methods and Results:Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalisation of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors.Conclusions:These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.
AU  - Kirkby,N
AU  - Raouf,J
AU  - Ahmetaj-Shala,B
AU  - Liu,B
AU  - Mazi,S
AU  - Edin,M
AU  - Geoffrey,Chambers M
AU  - Korotkova,M
AU  - Wang,X
AU  - Wahli,W
AU  - Zeldin,D
AU  - Nusing,R
AU  - Zhou,Y
AU  - Jakobsson,P-J
AU  - Mitchell,J
DO  - cvr/cvz290
EP  - 1980
PY  - 2020///
SN  - 0008-6363
SP  - 1972
TI  - Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis
T2  - Cardiovascular Research
UR  - http://dx.doi.org/10.1093/cvr/cvz290
UR  - http://hdl.handle.net/10044/1/74849
VL  - 116
ER  -

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