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J. Biol. Chem., Vol. 283, Issue 28, 19456-19464, July 11, 2008

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LOX-1 Receptor Blockade Abrogates oxLDL-induced Oxidative DNA Damage and Prevents Activation of the Transcriptional Repressor Oct-1 in Human Coronary Arterial Endothelium^*

Thomas Thum and Jürgen Borlak¹

From the Medizinische Klinik I, Kardiologie, Julius-Maximilians Universität, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany and the Center for Drug Research and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, 30625 Hannover, Germany

Activation of the lectin-like oxLDL receptor (LOX-1) promotes atherosclerosis. Oxidized LDL (oxLDL) increases production of reactive oxygen species (ROS) and leads to the development of endothelial dysfunction. The molecular causes for oxLDL to induce oxidative DNA damage and metabolic dysfunction remain uncertain. Here we report treatment of cultured human coronary arterial endothelial cells (HCAEC) with oxLDL to cause oxidative DNA damage as determined by a 3-fold increase in 8-OH-desoxyguanosine adduct formation and a 4-fold induction of the growth arrest and DNA damage-inducible transcripts GADD45 and GADD153. Oxidative stress resulted in activation of Oct-1, a transcriptional repressor of various vascular cytochrome P450 (CYP) monooxygenases. Activation of Oct-1 was protein kinase C (PKC)-mediated. Binding of Oct-1 to promoter sequences of CYP monooxygenases was increased upon treatment of HCAEC with oxLDL. This resulted in repressed production of endothelium-derived hyperpolarization factor 11,12-epoxyeicosatrieonic acid. Small interference RNA-mediated functional knockdown of Oct-1 prevented oxLDL-mediated silencing of CYP expression. Inhibition of LOX-1 attenuated oxLDL-mediated endothelial DNA damage, Oct-1/DNA binding, and reversed impaired production of EDHF. Taken collectively, oxLDL induced oxidative DNA damage and activation of Oct-1 to result in metabolic dysfunction of coronary arterial endothelium.

Received for publication, October 5, 2007 , and in revised form, April 1, 2008.

^* This work was supported in part by grants from the IZKF-Nachwuchsgruppe Cardiac Wounding and Healing (E-31, to T. T.). 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 Tables S1 and S2.

¹ To whom correspondence should be addressed: Fraunhofer Inst. of Toxicology and Experimental Medicine, Centre for Drug Research and Medical Biotechnology, Nikolai-Fuchs-Str. 1, D-30625 Hannover, Germany. Tel.: 49-511-5350-559; Fax: 49-511-5350-573; E-mail: borlak{at}item.fraunhofer.de.

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