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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1416.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A cis-Acting Region Regulates Oxidized Lipid-Mediated Induction of the Human Heme Oxygenase-1 Gene in Endothelial Cells

Nathalie Hill-Kapturczak; Christy Voakes; Jairo Garcia; Gary Visner; Harry S. Nick; Anupam Agarwal

From the Department of Medicine, Division of Nephrology, Hypertension and Transplantation (N.H.-K., C.V., J.G., A.A.), Department of Pediatrics (G.V.), Department of Neuroscience (H.S.N.), and Department of Biochemistry and Molecular Biology (H.S.N., A.A.), University of Florida, Gainesville, Fla.

Correspondence to Anupam Agarwal, MD, Division of Nephrology, Hypertension and Transplantation, Box 100224 JHMHC, 1600 SW Archer Rd, University of Florida, Gainesville, FL 32610. E-mail agarwal{at}nersp.nerdc.ufl.edu

Objective— Several proatherogenic agents including oxidized LDL and its major component, 13-hydroperoxyoctadecadienoic acid (13-HPODE), upregulate heme oxygenase-1 (HO-1). Our previous studies have demonstrated that 13-HPODE-mediated HO-1 induction occurs via transcriptional mechanisms. The purpose of this study was to evaluate the molecular regulation and identify the signaling pathways involved in 13-HPODE-mediated HO-1 induction in human aortic endothelial cells.

Methods and Results— The half-life of HO-1 mRNA after stimulation with 13-HPODE was 1.8 hours. Antioxidants such as N-acetylcysteine, iron chelation with deferoxamine mesylate, and protein kinase C inhibition with Gö6976 blocked HO-1 induction. Using promoter constructs up to 9.1 kb, no significant reporter activity was observed in response to 13-HPODE. A 13-HPODE-inducible DNase I hypersensitive site was identified that maps to a region 10 to 11 kb from the transcription start site of the human HO-1 gene. Based on the DNase I analysis, a -11.6-kb human HO-1 promoter construct was generated and elicited a 2.5-fold increase in reporter activity, indicating that 13-HPODE-mediated human HO-1 induction requires, at least in part, sequences that reside between 9.1 and 11.6 kb of the human HO-1 promoter.

Conclusions— Elucidation of the molecular mechanisms which control HO-1 gene expression will allow us to develop therapeutic strategies to enhance the cytoprotective potential of HO-1 in atherosclerosis.

Key Words: atherosclerosis • heme oxygenase-1 • gene transcription • chromatin structure • oxidized LDL

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