Author:
Azad Priti,Villafuerte Francisco C.,Bermudez Daniela,Patel Gargi,Haddad Gabriel G.
Abstract
AbstractMonge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a+ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.
Funder
U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute
Publisher
Springer Science and Business Media LLC
Subject
Clinical Biochemistry,Molecular Biology,Molecular Medicine,Biochemistry
Reference79 articles.
1. Beall, C. M. et al. Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am. J. Phys. Anthropol. 106, 385–400 (1998).
2. Bigham, A. W. et al. Identifying positive selection candidate loci for high-altitude adaptation in Andean populations. Hum. Genomics 4, 79–90 (2009).
3. Monge, C., Arregui, C. A. & Leonvelarde, F. Pathophysiology and epidemiology of chronic mountain-sickness. Int. J. Sports Med. 13, S79–S81 (1992).
4. Monge, C., Leonvelarde, F. & Arregui, A. Increasing prevalence of excessive erythrocytosis with age among healthy high-altitude miners. N. Engl. J. Med. 321, 1271–1271 (1989).
5. Monge, C., Lozano, R. & Whittembury, J. Effect of blood-letting on chronic mountain sickness. Nature 207, 770 (1965).
Cited by
26 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献