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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1416-1422
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

Keywords

  • Atherosclerosis
  • Chromatin structure
  • Gene transcription
  • Heme oxygenase-1
  • Oxidized LDL

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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