Titre
Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Kirkby, N.S.
Auteure/Auteur
Raouf, J.
Auteure/Auteur
Ahmetaj-Shala, B.
Auteure/Auteur
Liu, B.
Auteure/Auteur
Mazi, S.I.
Auteure/Auteur
Edin, M.L.
Auteure/Auteur
Chambers, M.G.
Auteure/Auteur
Korotkova, M.
Auteure/Auteur
Wang, X.
Auteure/Auteur
Wahli, W.
Auteure/Auteur
Zeldin, D.C.
Auteure/Auteur
Nüsing, R.
Auteure/Auteur
Zhou, Y.
Auteure/Auteur
Jakobsson, P.J.
Auteure/Auteur
Mitchell, J.A.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1755-3245
Statut éditorial
Publié
Date de publication
2020-10-01
Volume
116
Numéro
12
Première page
1972
Dernière page/numéro d’article
1980
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
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.
PID Serval
serval:BIB_D291322BFEBC
PMID
Open Access
Oui
Date de création
2021-01-13T09:06:13.365Z
Date de création dans IRIS
2025-05-21T04:34:50Z
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Nom
31688905_BIB_D291322BFEBC.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
927.62 KB
Format
Adobe PDF
PID Serval
serval:BIB_D291322BFEBC.P001
URN
urn:nbn:ch:serval-BIB_D291322BFEBC2
Somme de contrôle
(MD5):1a841d6a0401fdf95a89e6731d4a395c