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J. Biol. Chem., Vol. 278, Issue 51, 51006-51014, December 19, 2003

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Oxidized Phospholipids Induce Expression of Human Heme Oxygenase-1 Involving Activation of cAMP-responsive Element-binding Protein^*

Gerhard Krönke, Valery N. Bochkov, Joakim Huber, Florian Gruber, Stefan Blüml, Alexander Fürnkranz, Alexandra Kadl, Bernd R. Binder, and Norbert Leitinger

From the Department of Vascular Biology and Thrombosis Research, University of Vienna, Vienna A-1090, Austria

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, protects against oxidative stress, and shows potent anti-inflammatory effects. Oxidized phospholipids, which are generated during inflammation and apoptosis, modulate the inflammatory response by inducing the expression of several genes including HO-1. Here we investigated the signaling pathways and transcriptional events involved in the induction of HO-1 gene expression by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) in human umbilical vein endothelial cells. OxPAPC up-regulated HO-1 mRNA and protein in a time- and concentration-dependent manner, whereas pro-inflammatory agents like TNF- and lipopolysaccharide did not significantly induce HO-1 expression in human umbilical vein endothelial cells. Signaling pathways involved in the OxPAPC-mediated HO-1 induction included protein kinases A and C, as well as the mitogen-activated protein kinases p38 and ERK. The cAMP-responsive element-binding protein (CREB) was phosphorylated via these pathways in response to OxPAPC treatment and expression of a dominant-negative mutant of CREB inhibited OxPAPC-induced activity of a human heme oxygenase-1 promoter-driven luciferase reporter construct. We identified a cAMP-responsive element and a Maf recognition element to be involved in the transcriptional activation of the HO-1 promoter by OxPAPC. In gel shift assays we observed binding of CREB to the cAMP-responsive element after OxPAPC treatment. Induction of HO-1 expression by lipid oxidation products via CREB may represent a feedback mechanism to limit inflammation and associated tissue damage.

Received for publication, April 18, 2003 , and in revised form, August 4, 2003.

^* This work was supported by a grant from the österreichische National Bank and by Fonds zur Förderung wissenschaftlicher Forschung Grant P16086. 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.

To whom correspondence should be addressed: Dept. of Vascular Biology and Thrombosis Research, University of Vienna, Schwarzspanierstr. 17, Vienna A-1090, Austria. Tel.: 43-1-4277-62507; Fax: 43-1-4277-9625; E-mail: norbert.leitinger{at}univie.ac.at.

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