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 Bishopric, Keith A Webster

Research output: Contribution to journalArticle

223 Citations (Scopus)

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
Pages (from-to)894-899
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume245
Issue number3
DOIs
StatePublished - Apr 28 1998

Fingerprint

Hypoxia-Inducible Factor 1
Endothelin-1
Endothelial cells
Genes
Binding Sites
Endothelial Cells
Mutagenesis
Peptide Hormones
Transcription Initiation Site
Vasoconstrictor Agents
Site-Directed Mutagenesis
Transition metals
Myocardial Ischemia
Assays
Ischemia
Heart Failure
Gels
Metals
Mutation
Hypoxia

Keywords

  • ET-1
  • HRE
  • Ischemia
  • Vascular endothelium

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. / Hu, Jing; Discher, Daryl J.; Bishopric, Nanette; Webster, Keith A.

In: Biochemical and Biophysical Research Communications, Vol. 245, No. 3, 28.04.1998, p. 894-899.

Research output: Contribution to journalArticle

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