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Keratinocyte-Derived Vascular Endothelial Growth Factor Biosynthesis Represents a Pleiotropic Side Effect of Peroxisome Proliferator-Activated Receptor- Agonist Troglitazone but Not Rosiglitazone and Involves Activation of p38 Mitogen-Activated Protein Kinase: Implications for Diabetes-Impaired Skin Repair

Pharmazentrum Frankfurt/ZAFES (D.S., O.S., I.G., J.P.D., H.S., M.B., G.G., J.P., S.F.) and Zentrum der Chirurgie (R.S.), Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

The peroxisome proliferator-activated receptors (PPARs) represent pharmacological target molecules to improve insulin resistance in type 2 diabetes mellitus. Here we assessed a functional connection between pharmacological activation of PPAR and vascular endothelial growth factor (VEGF) expression in keratinocytes and during diabetes-impaired acute skin repair in obese/obese (ob/ob) mice. PPARβ/ agonist 4-[3-[4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid (L165,041) and PPAR agonists ciglitazone and troglitazone, but not rosiglitazone, potently induced VEGF mRNA and protein expression from cultured keratinocytes. Inhibitor studies revealed a strong functional dependence of troglitazone- and L165,041-induced VEGF expression on p38 and p42/44 mitogen-activated protein kinase (MAPK) activation in keratinocytes. Rosiglitazone also induced activation of p38 MAPK but failed to mediate the activation of p42/44 MAPK in the cells. Functional ablation of PPARβ/ and PPAR from keratinocytes by small interfering RNA did not abrogate L165,041- and troglitazone-induced VEGF biosynthesis and suggested VEGF induction as a pleiotropic, PPAR-independent effect of both drugs in the cells. In accordance with the in vitro situation, we found activated p38 MAPK in wound keratinocytes from acute wounds of rosiglitazone- and troglitazone-treated diabetic obese/obese mice, whereas keratinocyte-specific VEGF protein signals were only prominent upon troglitazone treatment. In summary, our data from cell culture and wound healing experiments suggested p38 MAPK activation as a side effect of thiazolidinediones; however, only troglitazone, but not rosiglitazone, seemed to translate p38 MAPK activation into a PPAR-independent induction of VEGF from keratinocytes.

Received for publication June 2, 2008.

Accepted for publication July 1, 2008.

Address correspondence to: Dr. Stefan Frank, Pharmazentrum Frankfurt/ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der JW Goethe-Universität Frankfurt/M., Theodor-Stern-Kai 7, D-60590 Frankfurt/M., Germany. E-mail: s.frank{at}em.uni-frankfurt.de