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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 alpha-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-alpha subunit by inhibiting its degradation through stabilization of its labile oxygen-dependent degradation domain. This is achieved through the inhibition of HIF-1alpha 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.

Original publication

DOI

10.1124/mol.108.045690

Type

Journal article

Journal

Mol Pharmacol

Publication Date

07/2008

Volume

74

Pages

282 - 288

Keywords

Animals, Aorta, Thoracic, Cattle, Cell Hypoxia, Cells, Cultured, Dose-Response Relationship, Drug, Genes, Reporter, HeLa Cells, Humans, Hydroxamic Acids, Hypoxia-Inducible Factor 1, Kinetics, Luciferases, Firefly, Male, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Metalloendopeptidases, Muscle, Smooth, Vascular, RNA Interference, RNA, Small Interfering, Rats, Rats, Wistar, Transfection