15-deoxy-Δ¹²,¹⁴ prostaglandin gJ₂ but not rosiglitazone regulates metalloproteinase 9, nos-2, and cyclooxygenase 2 expression and functions by peroxisome proliferatoractivated receptor γ-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 κB (NF-κB) and mitogen-activated protein kinase (MAPK), which play an important role in proinflammatory enzymes expression. It has been shown that 15-deoxy-Δ12,14 prostaglandin J2 (15dPGJ2) can repress the inflammatory response by means of peroxisome proliferator-activated receptor γ (PPARγ)-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 PPARγ-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 γ 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-κB and p38 MAPK, and we found that these signaling cascades are implicated in 15dPGJ2 action as well as PPARγ. These results suggest that only the natural PPARγ 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 PPARγ, showing NF-κB and p38 MAPK participation.