Protective role of estrogen against excessive erythrocytosis in Monge's disease.
Protective role of estrogen against excessive erythrocytosis in Monge's disease.
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DOI：
10.1038/s12276-020-00550-2
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发表时间：
2021-01
影响因子：
12.8
通讯作者：
Haddad GG
中科院分区：
文献类型：
--
作者：
Azad P;Villafuerte FC;Bermudez D;Patel G;Haddad GG
蒙格氏病(慢性高原病(CMS))是一种由于长期(多年)暴露在高原低氧环境中而导致的适应不良状况。CMS的特征之一是红细胞过多，红细胞压积极高。在安第斯山脉人群中，CMS的患病率在男性和女性之间差异很大，在女性中很少见。此外，绝经后女性CMS的发病率急剧增加。在这项研究中，我们评估了性激素(睾酮、孕酮和雌激素)在CMS和非CMS细胞中的作用，使用了一个具有良好特征的体外红系平台。虽然我们发现，在睾酮作用下，RBC产量有轻微(不显著)的增加，但我们观察到，在生理浓度下，雌激素以阶段特异性和剂量反应的方式急剧减少CD235a+细胞(血糖素A，RBC的标志)，从未处理的CMS细胞的56%降至处理的CMS细胞的10%。在分子水平上，我们确定雌激素对GATA1有直接作用，显著降低GATA1(p <； 0.001)及其靶基因(Alas2、BclxL和EpoR，p <； 0.01)的信使RNA和蛋白水平。这些变化导致红系细胞的凋亡率显著增加。我们还证明，雌激素通过雌激素β信号调节CMS患者的红细胞生成，其抑制可以通过显著增加HIF1、VEGF和GATA1的mRNA水平来减弱雌激素的影响。综上所述，我们的结果表明，雌激素对红细胞生成的调节有重要影响，特别是在慢性缺氧条件下，并具有治疗血液疾病的潜力，如高原重度红细胞增多症。雌激素激素可以预防绝经前女性的慢性高原病(CMS)，并可能被证明对治疗这种疾病很有价值。在高海拔山区生活多年的人，由于长期缺氧，容易患上CMS。CMS的一个因素是红细胞过度产生，使血液变稠，增加中风和心血管疾病的风险。男性比女性更容易患CMS，尽管更年期后女性的CMS病例会激增。美国圣地亚哥加利福尼亚大学的加布里埃尔·哈达德和他的同事使用CMS的细胞培养模型来证明雌激素提供了对疾病的保护。雌激素通过控制细胞死亡机制，显著改变红细胞相关基因的表达和活性，从而调节红细胞水平。
Monge’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. The hormone estrogen protects against chronic mountain sickness (CMS) in pre-menopausal women and may prove valuable in treating the condition. People who live for years in high altitude mountain regions are susceptible to CMS because of prolonged oxygen deprivation. One factor in CMS is an over-production of red blood cells, thickening the blood and increasing the risk of strokes and cardiovascular diseases. Men are more likely to suffer CMS than women, although cases spike in females after menopause. Gabriel Haddad at the University of California in San Diego, USA, and co-workers used a cell culture model of CMS to demonstrate that estrogen provides protection against the disease. Estrogen significantly alters the expression and activity of red blood cell-related genes to regulate red blood cell levels by controlling cell death mechanisms.
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SENP1通过GATA1和MONGE病的受试者通过GATA1和BCL-XL诱导低氧诱导的多性性疾病。
DOI：
10.1084/jem.20151920
发表时间：
2016-11-14
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Azad P;Zhao HW;Cabrales PJ;Ronen R;Zhou D;Poulsen O;Appenzeller O;Hsiao YH;Bafna V;Haddad GG
通讯作者：
Haddad GG
影响因子：
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作者：
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通讯作者：
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DOI：
10.1152/ajpendo.00184.2014
发表时间：
2014-09-01
影响因子：
5.1
作者：
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通讯作者：
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影响因子：
2.6
作者：
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通讯作者：
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影响因子：
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通讯作者：
Mormina M