Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 283, Issue 1, Pages L86-L93Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00476.2001
Keywords
pulmonary hypertension; hypoxia-inducible factor; reporter gene activity
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Funding
- NCRR NIH HHS [RR-164808] Funding Source: Medline
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The ovarian hormone 17beta-estradiol (E(2)beta) attenuates chronic hypoxia-induced pulmonary hypertension. We hypothesized that E(2)beta 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 h or 4 wk at barometric pressure = 380 mmHg) rats with intact ovaries and in hypoxic ovariectomized (OVX) rats administered E(2)beta or vehicle via subcutaneous osmotic pumps. Hypoxic exposure increased lung preproET-1 mRNA levels in OVX vehicle-treated rats, but not in rats with intact ovaries. In addition, E(2)beta 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 E(2)beta-induced attenuation of pulmonary ET-1 expression during hypoxia results from decreased HIF activity. We found that E(2)beta abolished HIF-dependent increases in reporter gene activity. Further experiments demonstrated that overexpression of the transcriptional coactivator cAMP response element binding protein (CREB) binding protein (CBP)/p300, a factor common to both the estrogen receptor and HIF pathways, eliminated E(2)beta-mediated attenuation of hypoxia-induced ET-1 promoter activity. We conclude that E(2)beta 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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