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J. Biol. Chem., Vol. 283, Issue 22, 15479-15490, May 30, 2008

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Biphasic Regulation of HMG-CoA Reductase Expression and Activity during Wound Healing and Its Functional Role in the Control of Keratinocyte Angiogenic and Proliferative Responses^*

Dana Schiefelbein, Itamar Goren, Beate Fisslthaler, Helmut Schmidt, Gerd Geisslinger, Josef Pfeilschifter, and Stefan Frank¹

From the Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany and the Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany

In this study, we determined the regulation and potential function of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) during skin repair in mice. Upon skin injury, healthy mice exhibited a biphasic increase in HMGR expression and activity with elevated levels at days 3 and 13 post-wounding. In situ hybridization revealed wound margin keratinocytes as a cellular source of HMGR expression. In vitro experiments using cultured HaCaT keratinocytes uncovered epidermal growth factor (EGF), transforming growth factor (TGF)-, and insulin as potent co-inducers of HMGR activity and vascular endothelial growth factor (VEGF) in the cells. Insulin-, but not EGF-mediated VEGF protein expression was functionally connected to co-induced HMGR activity, as simvastatin restrictively interfered only with insulin-induced translation of VEGF mRNA by inhibition of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation. Functional ablation of insulin-induced sterol regulatory element-binding protein (SREBP)-2 by siRNA abolished HMGR expression and insulin-triggered VEGF protein release from keratinocytes. Simvastatin also blocked proliferation of cultured keratinocytes. The observed inhibitory effects of simvastatin on keratinocyte VEGF expression and proliferation could be reversed by mevalonate, the product of HMGR enzymatic activity. In accordance, simvastatin-mediated inhibition of HMGR activity in acutely regenerating tissue of wounded mice was paralleled by a marked loss of VEGF protein expression and disturbances of normal proliferation processes in wound margin keratinocytes during skin repair.

Received for publication, December 3, 2007 , and in revised form, February 4, 2008.

^* This work was supported in part by the Deutsche Forschungsgemeinschaft (SFB 553, Grant FR 1540/1-2, GK 1172, Excellence Cluster Cardiopulmonary System) and by Eicosanox, EC FP6 funding (LSHM-CT-2005-005033). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: pharmazentrum frankfurt/ZAFES, Klinikum der JW Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main. Tel.: 49-69-6301-6955; Fax: 49-69-6301-7942; E-mail: S.Frank{at}em.uni-frankfurt.de.

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