PPAR activators and COX inhibitors selectively block cytokine-induced COX-2 expression and activity in human aortic smooth muscle cells.
Atherosclerotic complications are related to the unstable character of the plaque rather than its volume. Vulnerable plaques often contain a large lipid core, a reduced content of smooth muscle cells (SMCs), and an accumulation of inflammatory cells. Regulation of this inflammatory response is an essential element in chronic inflammatory diseases such as atherosclerosis. Nuclear receptors and particularly peroxisome proliferator-activated receptors (PPARs) have emerged as therapeutic targets with a widespread impact on the treatment of metabolic disorders because they can modulate gene expression involved in lipid and glucose homeostasis and can exert anti-inflammatory properties. However, little is known about nuclear receptor effects on SMC inflammation, which produces large amounts of IL-6 and prostanoids. The aim of this study was to evaluate anti-inflammatory properties of nuclear receptor activators in a human physiological SMC model. We show that PPAR activators, as well as liver X receptor alpha, farnesoid X receptor and retinoid X receptor alpha activators, inhibit IL-1beta-induced SMC 6-keto PGF1alpha synthesis, an index of cyclooxygenase (COX)-2 activity, with IC(50) between 1 and 69 microM. In contrast, PPARgamma activators, as exemplified by rosiglitazone and pioglitazone, were unable to inhibit cytokine-induced 6-keto PGF1alpha synthesis. We also demonstrate for the first time that the COX-2 inhibitor rofecoxib can reduce 6-keto PGF1alpha production by both enzymatic inhibition and transcriptional repression. These results show that some nuclear receptor activators have SMC anti-inflammatory properties due to COX-2 inhibition which could participate in their anti-atherosclerotic properties beyond lipid impacts.
Rival
Yves
Y
Centre de Recherche Pierre Fabre-17, Castres Cédex, France. yves.rival@pierre-fabre.com
Puech
Laurence
L
Taillandier
Thierry
T
Benéteau
Nathalie
N
Rouquette
Anne
A
Lestienne
Fabrice
F
Dupont-Passelaigue
Elisabeth
E
Le Roy
Isabelle
I
Patoiseau
Jean-François
JF
Junquéro
Didier
D
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology*; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
D016861:Cyclooxygenase Inhibitors; D053583:Interleukin-1beta; D015850:Interleukin-6; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger; D015121:6-Ketoprostaglandin F1 alpha; D051546:Cyclooxygenase 2