Received for publication January 28, 2008.
Revised April 15, 2008.
Accepted for publication April 16, 2008.

BiPS, a matrix metalloprotease inhibitor, is a novel and potent activator of hypoxia-inducible factors

Abstract

Hypoxia-inducible Factors (HIFs), unstable heterodimeric transcription factors, are 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 -subunit and permitting the formation of the 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- subunit by inhibiting its degradation through stabilization of its labile oxygen-dependent degradation domain. This is achieved through the inhibition of HIF- hydroxylation. The HIF-1 complex, formed following BiPS treatment, is capable of DNA binding and activation of HIF target genes including the expression of Vascular Endothelial Growth Factor. Since 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.

Key words: Regulation of gene expression, Transcription targets, Angiogenesis