15-deoxy-Delta12,14 prostaglandin GJ2 but not rosiglitazone regulates metalloproteinase 9, NOS-2, and cyclooxygenase 2 expression and functions by peroxisome proliferator-activated receptor gamma-dependent and -independent mechanisms in cardiac cells.
Sepsis or endotoxemia produced by LPS followed by hypotension and multiorganic failure may lead to cardiac dysfunction contributing to mortality. Cardiac failure is usually associated to activation of nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK), which play an important role in proinflammatory enzymes expression. It has been shown that 15-deoxy-Delta12,14 prostaglandin J2 (15dPGJ2) can repress the inflammatory response by means of peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent and -independent mechanisms. However, its precise role in heart is poorly understood. In the present study, mouse neonatal cardiomyocytes were isolated and stimulated with LPS to investigate the role of PPARgamma-specific ligands 15dPGJ2 and rosiglitazone on cardiac inflammatory response. Inducible NO synthase, cyclooxygenase 2, and metalloproteinase 9 mRNA levels, protein expression, and activity were inhibited with 15dPGJ2 but not by rosiglitazone. Peroxisome proliferator-activated receptor gamma antagonist, GW9662, prevented all these 15dPGJ2 actions. To go inside the mechanisms by which 15dPGJ2 exerts inhibitory effects, cells were preincubated with specific chemical inhibitors of NF-kappaB and p38 MAPK, and we found that these signaling cascades are implicated in 15dPGJ2 action as well as PPARgamma. These results suggest that only the natural PPARgamma ligand, 15dPGJ2, but not the synthetic one, rosiglitazone, regulates the inflammatory response by inhibition of inducible NO synthase, cyclooxygenase 2, and metalloproteinase 9 expression. Moreover, our results offer an additional 15dPGJ2 mechanism of action, despite PPARgamma, showing NF-kappaB and p38 MAPK participation.
Hovsepian
Eugenia
E
Centro de Estudios Farmacológicos y Botánicos (CEFYBO-CONICET-UBA), Buenos Aires, Argentina.
Penas
Federico
F
Goren
Nora B
NB
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D008070:Lipopolysaccharides; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009569:Nitric Oxide; C037112:9-deoxy-delta-9-prostaglandin D2; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone; D015230:Prostaglandin D2