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Articles in PresS, published online ahead of print February 8, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00476.2001
Submitted on December 13, 2001
Accepted on February 4, 2002
1 Department of Cell Biology and Physiology, University of New Mexico Health Science Center, Albuquerque, NM, USA
* To whom correspondence should be addressed. E-mail: searley{at}unm.edu.
The ovarian hormone 17ß-estradiol (E2-ß) attenuates chronic hypoxia-induced pulmonary hypertension. We hypothesized that E2-ß attenuates this response to hypoxia by decreasing pulmonary expression of the vasoactive and mitogenic peptide endothelin-1 (ET-1). To test this hypothesis, we measured preproET-1 mRNA and ET-1 peptide levels in the lungs of adult female normoxic and hypoxic (24 hr or 4 wk at PB = 380 mmHg) rats with intact ovaries, and hypoxic ovariectomized (OVX) rats administered E2-ß or vehicle via s.c. osmotic pumps. Hypoxic exposure increased lung preproET-1 mRNA levels in OVX vehicle-treated rats, but not in rats with intact ovaries. In addition, E2-ß replacement prevented hypoxia-mediated increases in preproET-1 mRNA and ET-1 peptide expression. Considering that hypoxic induction of ET-1 gene expression is mediated by a hypoxia-inducible transcription factor(s) (HIF), we further hypothesized that E2-ß-induced attenuation of pulmonary ET-1 expression during hypoxia results from decreased HIF activity. We found that E2-ß abolished HIF-dependent increases in reporter gene activity. Further experiments demonstrated that over-expression of the transcriptional co-activator CBP/p300, a factor common to both the estrogen receptor and HIF pathways, eliminated E2-ß-mediated attenuation of hypoxia-induced ET-1 promoter activity. We conclude that E2-ß inhibits hypoxic induction of ET-1 gene expression by interfering with HIF activity, possibly through competition for limiting quantities of CBP/p300.
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