PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPARgamma is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPARgamma in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPARgamma activator 15-deoxy-Delta12,14-prostaglandin J2 (15dPGJ2) increased promoter activity, whereas cotransfection of a dominant negative PPARgamma inhibited it. To determine the role of 15dPGJ2 in expression of proinflammatory genes, we tested its effect on interleukin-1beta induction of cyclooxygenase-2 (COX-2). 15dPGJ2 decreased interleukin-1beta stimulation of COX-2 by 40% and PGE2 production by 73%. We next questioned whether 15dPGJ2 was modulating the expression of inducible prostaglandin E2 synthase (PGES) and found that it completely blocked interleukin-1beta induction of PGES. Use of a second PPARgamma agonist, troglitazone, and the selective PPARgamma antagonist GW9662 demonstrated that the effects seen were PPARgamma-dependent. In addition, we found that 15dPGJ2 blocked interleukin-1beta stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ2 may play an anti-inflammatory role in a PPARgamma-dependent manner, decreasing COX-2, PGES, and PGE2 production, as well as iNOS expression.
Mendez
Mariela
M
Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202-2689, USA.
LaPointe
Margot C
MC
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D051546:Cyclooxygenase 2; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077288:Troglitazone
C477819:15-deoxyprostaglandin J2; C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002839:Chromans; D007375:Interleukin-1; D007527:Isoenzymes; D011453:Prostaglandins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D000077288:Troglitazone; D015230:Prostaglandin D2