Serum Inflammatory Factor Profiles in the Pathogenesis of High-Altitude Polycythemia and Mechanisms of Acclimation to High Altitudes.
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ABSTRACT:
SUBMITTER: Yi H
PROVIDER: S-EPMC8413029 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In high-altitude environments, the prevalence of high-altitude polycythemia (HAPC) ranges between 5 and 18 percent. However, there is currently no effective treatment for this condition. Therefore, disease prevention has emerged as a critical strategy against this disease. Here, we looked into the microarray profiles of GSE135109 and GSE29977, linked to either short- or long-term exposure to the Qinghai Tibet Plateau (QTP). The results revealed inhibition in the adaptive immune response during 30 days of exposure to QTP. Following a gene set enrichment analysis (GSEA) discovered that genes associated with HAPC were enriched in Cluster1, which showed a dramatic upregulation on the third day after arriving at the QTP. We then used GeneLogit to construct a logistic prediction model, which allowed us to identify 50 genes that classify HAPC patients. In these genes, LRRC18 and HCAR3 were also significantly altered following early QTP exposure, suggesting that they may serve as hub genes for HAPC development. The in-depth study of a combination of the datasets of transcriptomic changes during exposure to a high altitude and whether diseases occur after long-term exposure in Hans can give us some inspiration about genes associated with HAPC development during adaption to high altitudes.
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Project description:Developmental plasticity can elicit phenotypic adjustments that help organisms cope with environmental change, but the relationship between developmental plasticity and plasticity in adult life (e.g., acclimation) remains unresolved. We sought to examine developmental plasticity and adult acclimation in response to hypoxia of aerobic capacity (V̇O2max) for thermogenesis in deer mice (Peromyscus maniculatus) native to high altitude. Deer mice were bred in captivity and exposed to normoxia or one of four hypoxia treatments (12 kPa O2) across life stages: adult hypoxia (6-8 weeks), post-natal hypoxia (birth to adulthood), life-long hypoxia (before conception to adulthood), and parental hypoxia (mice conceived and raised in normoxia, but parents previously exposed to hypoxia). Hypoxia during perinatal development increased V̇O2max by a much greater magnitude than adult hypoxia. The amplified effect of developmental hypoxia resulted from physiological plasticity that did not occur with adult hypoxia - namely, increases in lung ventilation and volume. Evolved characteristics of deer mice enabled developmental plasticity, because white-footed mice (P. leucopus; a congener restricted to low altitudes) could not raise pups in hypoxia. Parental hypoxia had no persistent effects on V̇O2max. Therefore, developmental plasticity can have much stronger phenotypic effects and can manifest from distinct physiological mechanisms from adult acclimation.
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Project description:The yak is a valuable species in the Qinghai-Tibet Plateau of China. Nevertheless, the molecular mechanisms underlying its adaptation to high-altitude environments remain largely unknown. In the present study, comparative transcriptome sequencing was performed for lung and gluteus tissues from two species of low-altitude cattle (Sanjiang and Holstein cattle), Tibetan cattle (living at a moderate altitude), and yak (living at a high altitude) and the differentially expressed genes were validated using real-time quantitative PCR. The results showed that CD36 antigen was up-regulated and CD59 antigen was down-regulated in yak in comparison to the other animals, which might promote the development of red blood cells and inhibit the development of lymphocytes in yak. In addition, thrombospondin type 1, coagulation factor 5/8, and fibronectin were all down-regulated, but serpin and alpha 2-macroglobulin (A2M) were up-regulated. These differences would inhibit blood coagulation, thus reducing the risk of pulmonary edema. The expression levels of the calcium-release, potassium, and transient receptor potential channels decreased in yak, minimizing membrane depolarization and the harmful effects of pulmonary edema. Eleven KEGG pathways associated with innate immunity were more activated in yak and Tibetan cattle than in other cattle strains, which should reduce their risk of infection and disease. These changes together might facilitate the adaptation of yak and Tibetan cattle to live in high-altitude habitats.
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Project description:High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hypoxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeostasis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.
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Project description:BACKGROUND:High-altitude polycythemia (HAPC) is a chronic high-altitude disease that can lead to an increase in the production of red blood cells in the people who live in the plateau, a hypoxia environment, for a long time. The most frequent symptoms of HAPC include headache, dizziness, breathlessness, sleep disorders, and dilation of veins. Although chronic hypoxia is the main cause of HAPC, the fundamental pathophysiologic process and related molecular mechanisms responsible for its development remain largely unclear yet. AIM/METHODS:This study aimed to explore the related hereditary factors of HAPC in the Chinese Han and Tibetan populations. A total of 140 patients (70 Han and 70 Tibetan) with HAPC and 60 healthy control subjects (30 Han and 30 Tibetan) were recruited for a case-control association study. To explore the genetic basis of HAPC, we investigated the association between HAPC and both phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit delta gene (PIK3CD) and collagen type IV ?3 chain gene (COL4A3) in Chinese Han and Tibetan populations. RESULTS/CONCLUSION:Using the unconditional logistic regression analysis and the false discovery rate (FDR) calculation, we found that eight SNPs in PIK3CD and one SNP in COL4A3 were associated with HAPC in the Tibetan population. However, in the Han population, we did not find any significant association. Our study suggested that polymorphisms in the PIK3CD and COL4A3 were correlated with susceptibility to HAPC in the Tibetan population.
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Project description:The hypoxic environment imposes severe selective pressure on species living at high altitude. To understand the genetic bases of adaptation to high altitude in dogs, we performed whole-genome sequencing of 60 dogs including five breeds living at continuous altitudes along the Tibetan Plateau from 800 to 5100 m as well as one European breed. More than 150× sequencing coverage for each breed provides us with a comprehensive assessment of the genetic polymorphisms of the dogs, including Tibetan Mastiffs. Comparison of the breeds from different altitudes reveals strong signals of population differentiation at the locus of hypoxia-related genes including endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) and beta hemoglobin cluster. Notably, four novel nonsynonymous mutations specific to high-altitude dogs are identified at EPAS1, one of which occurred at a quite conserved site in the PAS domain. The association testing between EPAS1 genotypes and blood-related phenotypes on additional high-altitude dogs reveals that the homozygous mutation is associated with decreased blood flow resistance, which may help to improve hemorheologic fitness. Interestingly, EPAS1 was also identified as a selective target in Tibetan highlanders, though no amino acid changes were found. Thus, our results not only indicate parallel evolution of humans and dogs in adaptation to high-altitude hypoxia, but also provide a new opportunity to study the role of EPAS1 in the adaptive processes.
| S-EPMC4120084 | biostudies-literature
Project description:The low O2 experienced at high altitude is a significant challenge to effective aerobic locomotion, as it requires sustained tissue O2 delivery in addition to the appropriate allocation of metabolic substrates. Here, we tested whether high- and low-altitude deer mice (Peromyscus maniculatus) have evolved different acclimation responses to hypoxia with respect to muscle metabolism and fuel use during submaximal exercise. Using F1 generation high- and low-altitude deer mice that were born and raised in common conditions, we assessed 1) fuel use during exercise, 2) metabolic enzyme activities, and 3) gene expression for key transporters and enzymes in the gastrocnemius. After hypoxia acclimation, highland mice showed a significant increase in carbohydrate oxidation and higher relative reliance on this fuel during exercise at 75% maximal O2 consumption. Compared with lowland mice, highland mice had consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius. In contrast, only after hypoxia acclimation did activities of hexokinase increase significantly in the muscle of highland mice to levels greater than lowland mice. Highland mice also responded to acclimation with increases in muscle gene expression for hexokinase 1 and 2 genes, whereas both populations increased mRNA expression for glucose transporters. Changes in skeletal muscle with acclimation suggest that highland mice had an increased capacity for the uptake and oxidation of circulatory glucose. Our results demonstrate that highland mice have evolved a distinct mode of hypoxia acclimation that involves an increase in carbohydrate use during exercise.
| S-EPMC5401999 | biostudies-literature
Project description:High-altitude polycythemia (HAPC) is characterized by excessive proliferation of erythrocytes, resulting from the hypobaric hypoxia condition in high altitude. The genetic variants and molecular mechanisms of HAPC remain unclear in highlanders. We recruited 141 Tibetan dwellers, including 70 HAPC patients and 71 healthy controls, to detect the possible genetic variants associated with the disease; and performed targeted sequencing on 529 genes associated with the oxygen metabolism and erythrocyte regulation, utilized unconditional logistic regression analysis and GO (gene ontology) analysis to investigate the genetic variations of HAPC. We identified 12 single nucleotide variants, harbored in 12 genes, associated with the risk of HAPC (4.7 ≤ odd ratios ≤ 13.6; 7.6E - 08 ≤ p-value ≤ 1E - 04). The pathway enrichment study of these genes indicated the three pathways, the PI3K-AKT pathway, JAK-STAT pathway, and HIF-1 pathway, are essential, which p-values as 3.70E - 08, 1.28 E - 07, and 3.98 E - 06, respectively. We are hopeful that our results will provide a reference for the etiology research of HAPC. However, additional genetic risk factors and functional investigations are necessary to confirm our results further.Supplementary informationThe online version contains supplementary material available at 10.1007/s12288-021-01474-1.
| S-EPMC9209555 | biostudies-literature
Project description:Long term-exposed to high altitude, the increased numbers of red blood cells tend to stabilize to a certain extend in most people, but someone will occur over-increasing in number of red blood cells, which cause a serious of clinical symptoms and signs, and this is high altitude polycythemia. EPO-EPOR system may be the main reasons for erythroid progenitor cell proliferation and differentiation in early exposion to plateau, but, in the late, there may be other factors involved in the regulation of erythropoiesis in bone marrow, multiple factors working together lead to excessive red blood cell proliferation. We compared gene expression profiling of leukocytes in peripheral blood from high altitude polycythemia patients with those from matched controls. Subjects consisting of 5 masculine Han Chinese patients with HAPC (diagnosed according to international consensus statement on HAPC) and 5 matched controls, were migrants at River of TUOTUO area (Qinghai-Tibetan Plateau, 4550 m). Each of the five HAPC patients was matched to each of the control: gender, nationality, birthplace, duration migrating to plateau, height of location, work intensity. Peripheral blood samples were obtained at 4550m plateau from above subjects. Total RNA was extracted from peripheral blood leucocytes. The gene expression profilings were analysed by Human Genome U133 Plus 2.0 Array.
2014-06-15 | E-GEOD-29977 | biostudies-arrayexpress
Project description:BackgroundAs a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood.Methods37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis.ResultsThe results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent.ConclusionThis study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.
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