Physiological Adjustments and Circulating MicroRNA Reprogramming Are Involved in Early Acclimatization to High Altitude in Chinese Han Males

Abstract

Background: Altitude acclimatization is a physiological process that restores oxygen delivery to the tissues and promotes oxygen use under high altitude hypoxia. High altitude sickness occurs in individuals without acclimatization. Unraveling the molecular underpinnings of altitude acclimatization could help understand the beneficial body responses to high altitude hypoxia as well as the altered biological events in un-acclimatized individuals. This study assessed physiological adjustments and circulating microRNA (cmiRNA) profiles in individuals exposed to high altitude, aiming to explore altitude acclimatization in humans.Methods: Ninety volunteers were enrolled in this study. Among them, 22 individuals provided samples for microRNA arrays; 68 additional individuals constituted the validation set. Un-acclimatized individuals were identified by the Lake Louise Scoring System. Thirty-three phenotypes were recorded pre- and post-exposure to high altitude, including stress hormones, lipid profiles, hematological indices, myocardial enzyme spectrum, and liver and kidney function related enzymes. CmiRNA expression profiles were assessed using miRCURYTM LNA Array (v.18.0) screening, with data validated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Then, associations of plasma microRNA expression with physiological adjustments were evaluated. The biological relevance of the main differentially expressed cmiRNAs was explored by bioinformatics prediction.Results: Nineteen of the 33 phenotypes were significantly altered during early altitude acclimatization, including hematological indices, lipid profiles, and stress hormones; meanwhile, 86 cmiRNAs (79 up-regulated and 7 down-regulated) showed differential expression with statistical significance. Among them, 32 and 25 microRNAs were strongly correlated with low-density lipoprotein-cholesterol and total cholesterol elevations, respectively. In addition, 22 microRNAs were closely correlated with cortisol increase. In un-acclimatized individuals, 55 cmiRNAs were up-regulated and 36 down-regulated, compared with acclimatized individuals. The HIF signaling pathway was suppressed in un-acclimatized individuals.Conclusion: Physiological adjustments, including the hematological system, stress hormones, and lipid molecules contributed to early altitude acclimatization, and showed strong correlations with cmiRNA reprogramming. Moreover, acclimatized and un-acclimatized individuals showed different cmiRNA profile. Suppression of the HIF-1 signaling pathway by microRNA regulation may play a key role in the pathogenesis of un-acclimatization with high altitude hypoxia.

The OxymiR response to oxygen limitation: a comparative microRNA perspective

“…The above two studies focused on the miRNAs of native highaltitude acclimatized populations, and both plasma and RBC miRNA profiles revealed RBC-specific functionality, emphasizing the importance of tightly regulating miRNAs during hypoxic exposures. However, it is interesting to note that miRNAs have also been implicated in facilitating the acclimatization process and the restoration of oxygen delivery to tissues for individuals at high altitudes (Liu et al, 2016). The physiological adjustments observed during acclimatizationincluding those affecting hematology, stress hormones and lipid moleculeswere found to be strongly correlated with hypoxia-mediated regulation of circulating miRNAs (Liu et al, 2016), where 86 miRNAs (79 up-regulated and seven down-regulated) were significantly differentially expressed upon exposure to hypoxia.…”

“…However, it is interesting to note that miRNAs have also been implicated in facilitating the acclimatization process and the restoration of oxygen delivery to tissues for individuals at high altitudes (Liu et al, 2016). The physiological adjustments observed during acclimatizationincluding those affecting hematology, stress hormones and lipid moleculeswere found to be strongly correlated with hypoxia-mediated regulation of circulating miRNAs (Liu et al, 2016), where 86 miRNAs (79 up-regulated and seven down-regulated) were significantly differentially expressed upon exposure to hypoxia. Key functional targets of these circulating miRNAs include low-density lipoprotein-cholesterol, cholesterol metabolism and cortisol synthesis.…”

“…Key functional targets of these circulating miRNAs include low-density lipoprotein-cholesterol, cholesterol metabolism and cortisol synthesis. It is no surprise to find that HIF-1α signaling is significantly suppressed by miRNAs in unacclimated individuals (Liu et al, 2016). This inhibition of HIF-1α is likely to contribute to the pathogenesis and high-altitude sickness that unacclimated individuals experience, as HIF-1α signaling acts to promote adaptive responses to high altitude: one of its roles is to facilitate an increase in erythropoietin and aid oxygen delivery (Bigham and Lee, 2014).…”

Hematological Risk Factors for High-Altitude Headache in Chinese Men Following Acute Exposure at 3,700 m

“…Current studies regarding the pathophysiological etiology of HAH have suggested that HAH can be induced by hypobaric hypoxia causing overperfusion of the microvascular beds, brain swelling, activation of the trigeminal vascular system, and sensitization of intracranial pain receptors (Burtscher et al, 2011 ). Furthermore, the known independent risk factors for HAH include increased heart rate (HR), posterior cerebral circulation, vertebral artery diastolic velocity, and anxiety; decreased pulse oxygen saturation (SpO 2 ) and vigor; and a history of migraine or microRNA dysregulation (Silber et al, 2003 ; Lawley, 2011 ; Alizadeh et al, 2012 ; Bian et al, 2013 , 2015 ; Liu et al, 2016 ; Dong et al, 2017 ; Guo et al, 2017 ). However, the actual underlying mechanisms, clinical manifestations and risk factors/predictors remain not entirely clear, despite accumulating evidence regarding HAH (Marmura and Hernandez, 2015 ).…”

A Signature of Circulating microRNAs Predicts the Susceptibility of Acute Mountain Sickness

“…Replicated microRNAs were averaged, and probes with intensities ≥30 in all samples were selected for normalization. Detailed instructions were as previously described (Liu et al, 2016 ). After normalization, significantly differentially expressed microRNAs between the two groups were identified using Fold change and P -value cutoffs of 2 and 0.05, respectively.…”