Estrogen receptor‐dependent attenuation of hypoxia‐induced changes in the lung genome of pulmonary hypertension rats
العنوان: | Estrogen receptor‐dependent attenuation of hypoxia‐induced changes in the lung genome of pulmonary hypertension rats |
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المؤلفون: | Marjorie Albrecht, Andrea L. Frump, Tim Lahm, Jeanette N. McClintick |
المصدر: | Pulmonary Circulation |
بيانات النشر: | Wiley, 2017. |
سنة النشر: | 2017 |
مصطلحات موضوعية: | 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Microarray, medicine.drug_class, Estrogen receptor, Genome, 03 medical and health sciences, Internal medicine, medicine, pulmonary vasculature, Research Articles, Lung, fulvestrant, Fulvestrant, business.industry, 17β-estradiol, Hypoxia (medical), medicine.disease, Pulmonary hypertension, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Estrogen, Cardiology, Cancer research, medicine.symptom, gremlin 1, business, microarray, hormones, hormone substitutes, and hormone antagonists, medicine.drug |
الوصف: | 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/day) ± ER-antagonist ICI182,780 (3 mg/kg/day). 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 versus untreated hypoxia rats. Genes most upregulated by E2 encoded matrix metalloproteinase 8, S100 calcium binding protein A8, and IgA Fc receptor; genes most downregulated 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 upregulated by hypoxia, but found to be among the most downregulated genes after E2 treatment. Gremlin 1 protein was reduced in E2-treated versus 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. |
تدمد: | 2045-8940 |
الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::067be91a3fc24c39d83a8b3e1c507579Test https://doi.org/10.1177/2045893217702055Test |
حقوق: | OPEN |
رقم الانضمام: | edsair.doi.dedup.....067be91a3fc24c39d83a8b3e1c507579 |
قاعدة البيانات: | OpenAIRE |