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| Status |
Public on Aug 01, 2017 |
| Title |
Estrogen receptor-dependent attenuation of hypoxia-induced changes in the lung genome of pulmonary hypertension rats |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by array
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| Summary |
17β-estradiol (E2) exerts complex and context-dependent effects in pulmonary hypertension. In hypoxia-induced pulmonary hypertension (HPH), E2 attenuates lung vascular remodeling through estrogen receptor (ER)-dependent effects; however, ER target genes in the hypoxic lung remain unknown. In order to identify the genome regulated by the E2-ER axis in the hypoxic lung, we performed a microarray analysis in lungs from HPH rats treated with E2 (75 mcg/kg/d) ± ER-antagonist ICI182,780 (3 mg/kg/d). Untreated HPH rats and normoxic rats served as controls. Using a false discovery rate of 10%, we identified a significantly differentially regulated genome in E2-treated vs. untreated hypoxia rats. Genes most up-regulated by E2 encoded matrix metalloproteinase 8, S100 calcium binding protein A8, and IgA Fc receptor; genes most down-regulated by E2 encoded olfactory receptor 63, secreted frizzled-related protein 2, and thrombospondin 2. Several genes affected by E2 changed in the opposite direction after ICI182,780 co-treatment, indicating an ER-regulated genome in HPH lungs. The bone morphogenetic protein antagonist Grem1 (gremlin 1) was up-regulated by hypoxia, but found to be among the most down-regulated genes after E2 treatment. Gremlin 1 protein was reduced in E2-treated vs. untreated hypoxic animals, and ER-blockade abolished the inhibitory effect of E2 on Grem1 mRNA and protein. In conclusion, E2 ER-dependently regulates several genes involved in proliferative and inflammatory processes during hypoxia. Gremlin 1 is a novel target of the E2-ER axis in HPH. Understanding the mechanisms of E2 gene regulation in HPH may allow for selectively harnessing beneficial transcriptional activities of E2 for therapeutic purposes.
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| Overall design |
Hypoxia untreated and treated with 17β-estradiol alone and 17β-estradiol + fulvestrant are compared to normoxia in rat lung tissue.
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| Contributor(s) |
Lahm T, McClintick JN, Frump AL, Albrecht ME |
| Citation(s) |
28680582 |
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| Submission date |
Aug 15, 2016 |
| Last update date |
Nov 01, 2017 |
| Contact name |
Tim Lahm |
| E-mail(s) |
[email protected]
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| Phone |
317-278-0413
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| Organization name |
Indiana University
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| Street address |
980 W Walnut Street
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| City |
Indianapolis |
| ZIP/Postal code |
46250 |
| Country |
USA |
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| Platforms (1) |
| GPL6247 |
[RaGene-1_0-st] Affymetrix Rat Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA338957 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE85618_RAW.tar |
70.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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