Received for publication June 3, 2008.
Revised June 30, 2008.
Accepted for publication July 1, 2008.

Keratinocyte-derived VEGF biosynthesis represents a pleiotropic side effect of PPAR agonist troglitazone but not rosiglitazone and involves activation of p38 MAPK: implications for diabetes-impaired skin repair

Abstract

The peroxisome proliferator-activated receptors (PPAR) 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. PPAR/ agonist 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 MAPK activation in keratinocytes. Rosiglitazone also induced activation of p38 MAPK, but failed to mediate activation of p42/44 MAPK in the cells. Functional ablation of PPAR/ and PPAR from keratinocytes by small interfering RNA (siRNA) 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 to 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, appeared to translate p38 MAPK activation into a PPAR-independent induction of VEGF from keratinocytes.

Key words: PPARs, P38 MAP Kinase, Angiogenesis