15-deoxyprostaglandin-j2 and Body-Weight

Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation.

Topics: Angiotensin II; Anilides; Animals; Blood Pressure; Body Weight; Cell Proliferation; Cells, Cultured; Cyclin D1; Gene Expression Regulation; Hypoglycemic Agents; Kruppel-Like Transcription Factors; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Phosphorylation; PPAR gamma; Prostaglandin D2; Protein Kinase C; Rats; Rats, Sprague-Dawley; Rosiglitazone; Signal Transduction; Thiazolidinediones

Colitis involves immune cell-mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)gamma antagonist. We further demonstrate that Vanin-1, by antagonizing PPARgamma, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/pantetheinase activity might be a new target for therapeutic intervention in inflammatory bowel disease.

Topics: Active Transport, Cell Nucleus; Amidohydrolases; Animals; Benzhydryl Compounds; Body Weight; Cell Adhesion Molecules; Cell Line; Cell Nucleus; Chemokine CCL2; Chemokine CXCL2; Chemokines; Colitis; Colon; Cyclooxygenase 2; Cystamine; Cytokines; Epithelial Cells; Epoxy Compounds; Gene Expression Regulation; GPI-Linked Proteins; Interleukin-1beta; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; PPAR gamma; Prostaglandin D2; Survival Analysis; Trinitrobenzenesulfonic Acid