15-Deoxy-Δ12,14 PROSTAGLANDIN GJ2 BUT NOT ROSIGLITAZONE REGULATES METALLOPROTEINASE 9, NOS-2, AND CYCLOOXYGENASE 2 EXPRESSION AND FUNCTIONS BY PEROXISOME PROLIFERATORYACTIVATED RECEPTOR Γ-Dependent AND -INDEPENDENT MECHANISMS IN CARDIAC CELLS

Abstract

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.

In vitro effects of peroxisome proliferator–activated receptor-γ ligands on gene expression in lipopolysaccharide-induced endometrial and endometriotic stromal cells

“…From all these reports, it is clear that the effects of rosiglitazone depend not only on the doses of the drug but also on the cell type or the experimental model used. As far as treatment with 15d-PGJ 2 is concerned, our results are in accordance with reports in the literature (16,17).…”

Salmonella enterica Induces Joint Inflammation and Expression of Interleukin-17 in Draining Lymph Nodes Early after Onset of Enterocolitis in Mice

“…Quantification of gene expression was calculated using the comparative threshold cycle (C T ) method, normalized to the 18S control and efficiency of the reverse transcriptase reaction (relative quantity, 2 Ϫ⌬⌬CT ). The replicates were then averaged, and the fold induction was determined, with the value in the control group as 1 (23).…”

Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ12,14-Prostaglandin J2(15d-PGJ2) Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4+CD25−FOXP3+Cells

“…Reports have shown that 15d-PGJ 2 can repress some genes expression through the direct binding of ERK-MAPK and NF κ B [27, 28]. Furthermore, the proinflammatory production of NOS-2, metalloproteinase-2 (MMP-2), and MMP-9 as well as IL-6 and TNF- α in cultured cardiomyocytes infected with Trypanosoma cruzi , a protozoa parasite, was inhibited by administration of 15d-PGJ 2 , but rosiglitazone, a synthetic PPAR- γ agonist, was inefficient in inhibiting such mediators [29].…”