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J. Biol. Chem., Vol. 282, Issue 23, 16934-16941, June 8, 2007

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Photooxidation Generates Biologically Active Phospholipids That Induce Heme Oxygenase-1 in Skin Cells^*

Florian Gruber, Olga Oskolkova, Alexander Leitner^¶, Michael Mildner, Veronika Mlitz, Barbara Lengauer, Alexandra Kadl^||, Paul Mrass^**, Gerhard Krönke^¶, Bernd R. Binder, Valery N. Bochkov, Norbert Leitinger^||1, and Erwin Tschachler

From the Deparments of Dermatology and Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna 1090, Austria, the ^¶Department of Analytical Chemistry and Food Chemistry, University of Vienna, Vienna 1090, Austria, the ^||Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, the ^**Wistar Institute, Philadelphia, Pennsylvania 19104, and CE.R.I.E.S, Neuilly sur Seine 92200, France

Heme oxygenase-1 (HO-1) is a key enzyme in the cellular response to tissue injury and oxidative stress. HO-1 enzymatic activity results in the formation of the cytoprotective metabolites CO and biliverdin. In the skin, HO-1 is strongly induced after long wave ultraviolet radiation (UVA-1). Here we show that UVA-1 irradiation generates oxidized phospholipids derived from 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) that mediate the expression of HO-1 in skin cells. Using EO6 antibodies that recognize oxidized phospholipids, we show that UVA-1 irradiation of dermal fibroblasts generates oxidation-specific epitopes. Irradiation of arachidonate-containing phospholipids with UVA-1 led to formation of defined lipid oxidation products including epoxyisoprostane-phosphatidylcholine that induced HO-1 expression in dermal fibroblasts, in keratinocytes, and in a three-dimensional epidermal equivalent model. In addition, we demonstrate that the oxidation of PAPC by UVA-1 is a singlet oxygen-dependent mechanism. Together, we present a novel mechanism of UVA-1-induced HO-1 expression that is mediated by the generation of biologically active phospholipid oxidation products. Because UVA-1 irradiation is a mainstay treatment of several inflammatory skin diseases, structural identification of UVA-1-generated biomolecules with HO-1-inducing capacity should lead to the development of drugs that could substitute for irradiation.

Received for publication, March 23, 2007

^* This work was supported in part by National Institutes of Health Grant RO1 HL084422-01 (to N. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ To whom correspondence should be addressed: Cardiovascular Research Center, University of Virginia, P.O. Box 801394 Charlottesville, VA 22908. Tel.: 434-243-6363; Fax: 434-924-2828; E-mail: nl2q{at}virginia.edu.

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