Abstract
Hypoxia-inducible factors (HIFs) are unstable heterodimeric transcription factors and decisive elements for the transcriptional regulation of genes important in the adaptation to low-oxygen conditions. Hypoxia is the ubiquitous inducer of HIFs, stabilizing the α-subunit and permitting the formation of a functional HIF complex. Here, we identify (2R)-[(4-biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide (BiPS), a commercially available metalloprotease-2 and -9 inhibitor, as a rapid and potent inducer of HIFs. We show that in different cell lines, BiPS induces the HIF-α subunit by inhibiting its degradation through stabilization of its labile oxygen-dependent degradation domain. This is achieved through the inhibition of HIF-1α hydroxylation. The HIF-1 complex, formed after BiPS treatment, is capable of DNA binding and activation of HIF target genes, including the expression of vascular endothelial growth factor. Because novel HIF activators have generated considerable interest in the possible treatment of different ischemic diseases, we believe that BiPS and derivative molecules could have strong therapeutic potential.
Footnotes
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This work was supported by grants from the Canadian Institutes of Health Research (CIHR, MOP-49609) and the Heart and Stroke Foundations of Québec and Canada. D.E.R. is a recipient of a CIHR New Investigator Award. M.C.L. is a recipient of a Graduate Scholarship from the CIHR.
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ABBREVIATIONS: HIF, hypoxia-inducible factor; PHD, hypoxia-inducible factor prolyl hydroxylase; ODDD, oxygen-dependent degradation domain; pVHL, von Hippel Lindau protein; MMP, matrix metalloprotease; BAEC, bovine aortic endothelial cell; VSMC, vascular smooth muscle cell; 2-OG, 2-oxoglutarate; BiPS, (2R)-[(4-biphenylylsulfonyl)amino]-N-hydroxy-3-phenylpropionamide; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leuleucinal; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; siRNA, small interfering RNA; NETN buffer, NaCl, EDTA, Tris, Igepal, and deferoxamine; HA, hemagglutinin; HRE, hypoxia response element; PAGE, polyacrylamide gel electrophoresis; MAPK, mitogen-activated protein kinase; DMSO, dimethyl sulfoxide; GM6001, galardin.
- Received January 25, 2008.
- Accepted April 16, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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