Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of
hypoxia-inducible genes. The matrix
proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of
versican by
hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that
versican mRNA is up-regulated much more highly (>600 fold) by long term
hypoxia (5 days) than by 1 day of
hypoxia (48 fold). We report that
versican mRNA decay rates are not affected by
hypoxia, demonstrating that hypoxic induction of
versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of
luciferase reporter constructs in human macrophages. The
hypoxia-inducible
transcription factor HIF-1 has previously been implicated as a key potential regulator of
versican expression in
hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of
Phosphoinositide 3-kinase (PI3K),
LY290042 and
wortmannin, significantly reduced induction of
versican mRNA by
hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of
versican expression.