The Genetic Architecture of Chronic Mountain Sickness in Peru

Gazal, Steven; Espinoza, J.R.; Austerlitz, Frédéric; Marchant, Dominique; Macarlupú, José Luis; Rodríguez, Jorge; Ju-Preciado, Hugo; Rivera-Chira, María; Hermine, Olivier; León‐Velarde, Fabiola; Villafuerte, Francisco C.; Richalet, Jean‐Paul; Gouya, Laurent

doi:10.3389/fgene.2019.00690

Cited by 14 publications

(11 citation statements)

References 70 publications

(136 reference statements)

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“…Our group and others have found a number of candidate genes that are differentially expressed when CMS are compared with non-CMS subjects. Others have corroborated our findings in this field, such as the role of the desumoylase SENP1, which has been confirmed by other groups [38][39][40] . Furthermore, using induced pluripotent stem (iPS)-derived cells from this unique Andean population, we have developed an in vitro model that mimics hypoxia-induced excessive polycythemia in CMS subjects 36 .…”

Section: Introductionsupporting

confidence: 91%

Protective role of estrogen against excessive erythrocytosis in Monge’s disease

et al. 2021

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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.

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Section: Introductionsupporting

confidence: 91%

Protective role of estrogen against excessive erythrocytosis in Monge’s disease

et al. 2021

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“…People at high altitudes (≥2500 m) would suffer from acute mountain sickness (AMS) or chronic mountain sickness (CMS), manifested by headache, insomnia, and dyspnea ( Ma et al, 2020 ). Besides, AMS simultaneously causes nausea, vomiting, and dizziness, and can even be life threatening, while CMS can result in dyspepsia and high risk of thrombosis, affecting more than 80 million people worldwide ( Gazal et al, 2019 ). Some evidences show that the prevalence of CMS in high-altitude populations varies from 1.2 to 33% ( Bao et al, 2017 ) and is about 20% among Andean highlanders ( Yao et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Tibetan Medicine Duoxuekang Capsule Ameliorates High-Altitude Polycythemia Accompanied by Brain Injury

Chen

Fan

et al. 2021

Front. Pharmacol.

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Objective: Duoxuekang (DXK) capsule is an empirical prescription for Tibetan medicine in the treatment of hypobaric hypoxia (HH)-induced brain injury in the plateau. This study aimed to investigate the protective effects and underlying molecular mechanisms of DXK on HH-induced brain injury.Methods: UPLC–Q-TOF/MS was performed for chemical composition analysis of DXK. The anti-hypoxia and anti-fatigue effects of DXK were evaluated by the normobaric hypoxia test, sodium nitrite toxicosis test, and weight-loaded swimming test in mice. Simultaneously, SD rats were used for the chronic hypobaric hypoxia (CHH) test. RBC, HGB, HCT, and the whole blood viscosity were evaluated. The activities of SOD and MDA in the brain, and EPO and LDH levels in the kidney were detected using ELISA. H&E staining was employed to observe the pathological morphology in the hippocampus and cortex of rats. Furthermore, immunofluorescence and Western blot were carried out to detect the protein expressions of Mapk10, RASGRF1, RASA3, Ras, and IGF-IR in the brain of rats. Besides, BALB/c mice were used for acute hypobaric hypoxia (AHH) test, and Western blot was employed to detect the protein expression of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 in the cerebral cortex of mice.Results: 23 different chemical compositions of DXK were identified by UPLC–Q-TOF/MS. The anti-hypoxia test verified that DXK can prolong the survival time of mice. The anti-fatigue test confirmed that DXK can prolong the swimming time of mice, decrease the level of LDH, and increase the hepatic glycogen level. Synchronously, DXK can decrease the levels of RBC, HGB, HCT, and the whole blood viscosity under the CHH condition. Besides, DXK can ameliorate CHH-induced brain injury, decrease the levels of EPO and LDH in the kidney, reduce MDA, and increase SOD in the hippocampus. Furthermore, DXK can converse HH-induced marked increase of Mapk10, RASGRF1, and RASA3, and decrease of Ras and IGF-IR. In addition, DXK can suppress the ratio of p-ERK/ERK, p-JNK/JNK, and p-p38/p38 under the HH condition.Conclusion: Together, the cerebral protection elicited by DXK was due to the decrease of hematological index, suppressing EPO, by affecting the MAPK signaling pathway in oxidative damage, and regulating the RAS signaling pathway.

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“…Importantly, exercise training limited the weight gain of our rats. As obesity increases the risk of developing CMS and the severity of the condition (Gazal et al, 2019; Rivera‐Ch et al, 2007), limiting weight increase is of particular interest. Conversely, in sedentary rats, we observed after one month a decrease in time to exhaustion and in maximum speed, probably due to the increase in body weight.…”

Section: Discussionmentioning

confidence: 99%