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Expression During Hypoxia1
Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Peroxisome proliferator-activated receptors (PPARs) are nuclear
hormone-binding proteins that regulate transcriptional responses to
peroxisome proliferators and structurally diverse fatty acids. PPARs
have been implicated in a wide variety of functions, including lipid
homeostasis and inflammatory responses. In this study, we examined the
expression of PPAR-
in response to ambient hypoxia. Initial studies
using microarray analysis of intestinal epithelial mRNA revealed that
hypoxia rapidly down-regulates PPAR- mRNA and protein in epithelial
cells in vitro and in vivo. Subsequent studies revealed that the
PPAR- gene bears a DNA consensus motif for the transcription
factor hypoxia-inducible factor 1 (HIF-1). EMSA analysis revealed that
ambient hypoxia induces HIF-1 binding to the HIF-1 consensus domain
of PPAR- in parallel to HIF-1 nuclear accumulation, and antisense
depletion of HIF-1 resulted in a loss of PPAR- down-regulation.
The PPAR- ligand pirinixic acid (WY14643) functionally
promoted IFN-
-induced ICAM-1 expression in normoxic epithelia, and
this response was lost in cells pre-exposed to ambient hypoxia. Such
results indicate that HIF-1-dependent down-regulation of PPAR- may
provide an adaptive response to proinflammatory stimuli during cellular
hypoxia. These studies provide unique insight into the regulation of
PPAR- expression and, importantly, provide an example of a
down-regulatory pathway mediated by HIF-1.
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