Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.

Details

Serval ID
serval:BIB_D291322BFEBC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.
Journal
Cardiovascular research
Author(s)
Kirkby N.S., Raouf J., Ahmetaj-Shala B., Liu B., Mazi S.I., Edin M.L., Chambers M.G., Korotkova M., Wang X., Wahli W., Zeldin D.C., Nüsing R., Zhou Y., Jakobsson P.J., Mitchell J.A.
ISSN
1755-3245 (Electronic)
ISSN-L
0008-6363
Publication state
Published
Issued date
01/10/2020
Peer-reviewed
Oui
Volume
116
Number
12
Pages
1972-1980
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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 endothelial nitric oxide synthase, 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.
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 compartmentalization 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.
These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.
Keywords
PGE2, ADMA, COX-2, Methylarginines, Non-steroidal anti-inflammatory drugs, Prostacyclin, Vioxx, PGE2
Pubmed
Web of science
Open Access
Yes
Create date
13/01/2021 11:06
Last modification date
28/05/2021 6:36
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