Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand

Jing Hu, Daryl J. Discher, Nanette H. Bishopric, Keith A. Webster

Research output: Contribution to journalArticle

226 Scopus citations

Abstract

Endothelin-1 (ET-1) is a peptide hormone with potent vasoconstrictor properties that is synthesized and secreted predominantly by vascular endothelial cells. Its production is regulated by numerous stimuli including ischemia and hypoxia, and the enhanced levels that occur during myocardial ischemia may contribute to the progression of heart failure. We previously reported that ET-1 expression was induced by both hypoxia and transition metals in endothelial cells (ECs). Here we define an element in the proximal promoter of the ET-1 gene that is responsible for this induction. By using deletions and site directed mutagenesis of the human ET-1 promoter, in combination with electrophoretic gel mobility shifts and transient expression assays in human ECs, we identified an active hypoxia-inducible factor 1 (HIF-1) binding site starting at position -118 upstream of the transcription start site on the non-coding DNA strand. Mutation of this site eliminated induction by hypoxia without affecting basal (aerobic) expression, and the mutated sequence did not display hypoxia-specific binding of HIF-1.

Original languageEnglish (US)
Pages (from-to)894-899
Number of pages6
JournalBiochemical and biophysical research communications
Volume245
Issue number3
DOIs
StatePublished - Apr 28 1998

Keywords

  • ET-1
  • HRE
  • Ischemia
  • Vascular endothelium

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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