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Cell-specific and hypoxia-dependent regulation of human HIF-3α: inhibition of the expression of HIF target genes in vascular cells

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Abstract

Hypoxia-inducible factors (HIF) are transcription factors responding to reduced oxygen levels and are of utmost importance for regulation of a widespread of cellular processes, e.g., angiogenesis. In contrast to HIF-1α/HIF-2α, the relevance of HIF-3α for the regulation of the HIF pathway in human vascular cells is largely unknown. HIF-3α mRNA increases under hypoxia in endothelial and vascular smooth muscle cells. Analysis of HIF-3α isoforms revealed a cell type-specific pattern, but only one isoform, HIF-3α2, is hypoxia-inducible. Reporter gene assays of the appropriate promoter localized a 31-bp fragment, mediating this hypoxic regulation. The contribution of HIF-1/2 and NFκB to the HIF-3α induction was verified. Functional studies focused on overexpression of HIF-3α isoforms, which decrease the hypoxia-mediated expression of VEGFA and Enolase2. These data support the notion of a hypoxia-induced inhibitory function of HIF-3α and demonstrate for the first time the existence of this negative regulation of HIF-signaling in vascular cells.

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Abbreviations

HIF:

Hypoxia-inducible factor

HRE:

Hypoxia response element

HUVEC:

Human umbilical venous endothelial cell

VSMC:

Vascular smooth muscle cell

DMSO:

Dimethylsulfoxid

DMOG:

Dimethyloxalylglycine

PHD:

Prolylhydroxylases

Ets:

e26 transformation-specific transcription factor

AP-1:

Activating protein-1 transcription factor

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Acknowledgments

We thank the Cardiosurgical Department at the Heart Center Dresden for providing tissue of human aortas at the time of coronary bypass grafting and Anita Männel for excellent technical assistance.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Internal Medicine and Cardiology, University of Technology Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Antje Augstein, David M. Poitz, Rüdiger C. Braun-Dullaeus, Ruth H. Strasser & Alexander Schmeisser

  2. Medical Clinic for Cardiology and Angiology, Magdeburg University, Leipziger Strasse 44, 39120, Magdeburg, Germany

    Rüdiger C. Braun-Dullaeus & Alexander Schmeisser

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  1. Antje Augstein
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  2. David M. Poitz
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  3. Rüdiger C. Braun-Dullaeus
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Correspondence to Antje Augstein.

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Augstein, A., Poitz, D.M., Braun-Dullaeus, R.C. et al. Cell-specific and hypoxia-dependent regulation of human HIF-3α: inhibition of the expression of HIF target genes in vascular cells. Cell. Mol. Life Sci. 68, 2627–2642 (2011). https://doi.org/10.1007/s00018-010-0575-4

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  • DOI: https://doi.org/10.1007/s00018-010-0575-4

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