title: Keratinocyte-derived vascular endothelial growth factor biosynthesis represents a pleiotropic side effect of peroxisome proliferator-activated receptor-gamma agonist troglitazone but not rosiglitazone and involves activation of p38 mitogen-activated protein kinase: implications for diabetes-impaired skin repair.
abstract: 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. PPARbeta/delta agonist 4-[3-[4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid (L165,041) and PPARgamma 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 PPARbeta/delta and PPARgamma 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 PPARgamma-independent induction of VEGF from keratinocytes.
authors.affiliation: 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.
authors.forename: Dana
authors.initials: D
authors.lastname: Schiefelbein
authors.forename: Oliver
authors.initials: O
authors.lastname: Seitz
authors.forename: Itamar
authors.initials: I
authors.lastname: Goren
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Dissmann
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Malte
authors.initials: M
authors.lastname: Bachmann
authors.forename: Robert
authors.initials: R
authors.lastname: Sader
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Stefan
authors.initials: S
authors.lastname: Frank
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000378:metabolism* / Q000494:pharmacology; D003920:Diabetes Mellitus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047495:PPAR gamma / Q000819:agonists*; D012333:RNA, Messenger / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism* / Q000494:pharmacology; D013997:Time Factors; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D002839:Chromans; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D000077154:Rosiglitazone; D048051:p38 Mitogen-Activated Protein Kinases; D000077288:Troglitazone