Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression.
The ovarian hormone 17beta-estradiol (E2beta) attenuates chronic hypoxia-induced pulmonary hypertension. We hypothesized that E2beta 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 E2beta 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, E2beta 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 E2beta-induced attenuation of pulmonary ET-1 expression during hypoxia results from decreased HIF activity. We found that E2beta 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 E2beta-mediated attenuation of hypoxia-induced ET-1 promoter activity. We conclude that E2beta inhibits hypoxic induction of ET-1 gene expression by interfering with HIF activity, possibly through competition for limiting quantities of CBP/p300.
Earley
Scott
S
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218, USA. searley@unm.edu
Resta
Thomas C
TC
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D016232:Endothelins / Q000235:genetics; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006400:Hematocrit; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008168:Lung / Q000187:drug effects / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014599:Uterus / Q000033:anatomy & histology
D004268:DNA-Binding Proteins; D019332:Endothelin-1; D016232:Endothelins; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D004958:Estradiol; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat