Application of UHPLC-MS/MS-based nontargeted metabolomics in plasma metabolism in altitude-related hypertension among high-altitude migrants

Chaocheng WANG; Caizhi TANG; Zhuang RAN; Yongjun LUO

doi:10.16016/j.2097-0927.202311001

您当前的位置：

首页 >

文章列表页 >

Application of UHPLC-MS/MS-based nontargeted metabolomics in plasma metabolism in altitude-related hypertension among high-altitude migrants

Military Medicine | 更新时间：2026-01-09

- Application of UHPLC-MS/MS-based nontargeted metabolomics in plasma metabolism in altitude-related hypertension among high-altitude migrants
- Journal of Army Medical University Vol. 46, Issue 19, Pages: 2249-2258(2024)
- 作者机构：
  
  1.400038 重庆，陆军军医大学(第三军医大学)陆军卫勤训练基地军事医学地理学教研室
  2.430070 武汉，中部战区总医院干部病房三科
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(42377466);the Special Project of Second Comprehensive Scientific Investigation and Research on Qinghai-Tibet Plateau From Ministry of Science and Technology(2019QZKK0607)
- DOI：10.16016/j.2097-0927.202311001
  CLC： R331.1;R394.2;R544.1
- Received：01 November 2023，
  
  Revised：2024-05-18，
  
  Published：15 October 2024
- 稿件说明：
移动端阅览
Chaocheng WANG, Caizhi TANG, Zhuang RAN, et al. Application of UHPLC-MS/MS-based nontargeted metabolomics in plasma metabolism in altitude-related hypertension among high-altitude migrants[J]. Journal of Army Medical University, 2024, 46(19): 2249-2258.
DOI：

Chaocheng WANG, Caizhi TANG, Zhuang RAN, et al. Application of UHPLC-MS/MS-based nontargeted metabolomics in plasma metabolism in altitude-related hypertension among high-altitude migrants[J]. Journal of Army Medical University, 2024, 46(19): 2249-2258. DOI： 10.16016/j.2097-0927.202311001.

摘要

目的

研究高原性高血压(altitude-related hypertension

ARH)患者和健康个体之间血浆代谢产物的差异，并分析ARH的潜在发病机制。

方法

选取2020年7月在进驻海拔4 200 m处的健康平原成年男性官兵中按简单随机抽样法选取20名ARH患者为ARH组，30名血压正常者为对照(Control)组。在测量血压、体质指数(body mass index

BMI)、血氧饱和度和心率后，采集研究对象空腹静脉血样本。基于超高效液相色谱-质谱联用(ultra-high performance liquid chromatography-tandem mass spectrometry

UHPLC-MS/MS)技术，对研究对象血浆中的代谢产物进行筛选和鉴定。使用无监督主成分分析(principal component analysis

PCA)和有监督的正交偏最小二乘判别分析(orthogonal partial least squares discrimination analysis

OPLS-DA)模型对代谢产物进行指纹图谱分析，以辅助生物标志物的筛选，并对OPLS-DA模型进行质量考查和验证，以确保模型的稳定性和可靠性。使用独立样本

检验和差异倍数(fold change

FC)分析，绘制火山图，筛选有差异的血浆代谢物。使用京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes，KEGG)富集通路分析对筛选出的差异性代谢物进行功能途径的富集分析和拓扑学分析。

结果

与Control组比较，ARH组的收缩压、舒张压和心率显著升高，动脉血氧饱和度显著降低(

＜0.05)。PCA分析显示，正离子模式下，解释了81.96%的变异；负离子模式下，解释了79.25%的变异，表明2组之间存在显著的代谢差异。OPLS-DA模型分析显示，正离子模式下，PC1解释了77.36%的变异，PC2解释了12.25%的变异，R

Y=0.96，Q

Y=0.91；负离子模式下，PC1解释了84.15%的变异，PC2解释了17.24%的变异，R

Y=0.99，Q

Y=0.86。组间差异均超过75%，组内差异均小于20%。正离子模式下，R

拟合直线的Y轴截距为0.58，Q

拟合直线的Y轴截距为-0.48；负离子模式下，R

拟合直线的Y轴截距为0.93，Q

拟合直线的Y轴截距为-0.41。共筛选出32种具有显著差异的代谢产物，包括氨基酸、核苷、脂肪酸和有机生物碱。KEGG分析显示，10条代谢通路中有4条为氨基酸代谢通路，氨酰-tRNA生物合成途径富集的代谢产物最多。

结论

基于UHPLC-MS/MS技术，运用非靶向代谢组学筛选出的32种具有明显差异的代谢产物可能作为ARH的特征性生物标志物，而氨酰-tRNA生物合成途径可能与ARH的发病机制相关。

Abstract

Objective

To investigate the differences in plasma metabolites between patients with altitude-related hypertension (ARH) and healthy individuals

and analyze the potential pathogenesis of ARH.

Methods

Convenient sampling was conducted on a unit of male healthy officers and soldiers who resident at altitude of < 500 m and migrated to an altitude of 4 200 m in July 2020. Twenty of them diagnosed with ARH were assigned into the ARH group

and another 30 non-ARH individuals served as the control group. Their blood pressure

body mass index (BMI)

blood oxygen saturation

and heart rate were measured and recorded

and fasting venous blood samples were harvested to screen and identify plasma metabolites with ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Metabolite fingerprinting was performed using unsupervised Principal Component Analysis (PCA) and supervised Orthogonal Partial Least Squares Discrimination Analysis (OPLS-DA) models in order to assist in biomarker screening. The quality of the OPLS-DA model was assessed and validated to guarantee the stability and reliability of the model. Differential plasma metabolites were screened using independent sample t test and fold change (FC) analysis

and volcano plots were drawn. Finally

Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis was used to perform functional pathway enrichment and topological analysis on the screened differential metabolites.

Results

Compared to the control group

the ARH group showed significantly higher systolic and diastolic blood pressure and heart rate

and lower arterial oxygen saturation (

0.05). PCA analysis showed that 81.96% of the variance was explained in the po

sitive ion mode and 79.25% in the negative ion mode

indicating significant metabolic differences between the 2 groups. OPLS-DA model analysis indicated that in the positive ion mode

PC1 explained 77.36% of the variance and PC2 explained 12.25% of the variance

with R

Y=0.96 and Q

Y=0.91; in the negative ion mode

PC1 explained 84.15% of the variance and PC2 explained 17.24% of the variance

with R

Y=0.99 and Q

Y=0.86. Inter-group difference exceeded 75%

and intra-group difference was less than 20%. The 7-fold cross-validation and 200 permutation test confirmed that the model was stable and reliable. In the positive ion mode

the Y-axis intercepts of the R

and Q

fitted lines were 0.58 and -0.48

respectively; in the negative ion mode

the Y-axis intercepts were 0.93 and -0.41

respectively. A total of 32 significantly different metabolites were screened out

including amino acids

nucleosides

fatty acids

and organic alkaloids. KEGG analysis revealed that among the 10 metabolic pathways

4 were amino acid metabolic pathways

with the aminoacyl-tRNA biosynthesis pathway having the most enriched metabolites.

Conclusion

Based on UHPLC-MS/MS technology

untargeted metabolomics analysis identifies 32 significantly different metabolites

which may serve as characteristic biomarkers for ARH

and the aminoacyl-tRNA biosynthesis pathway may be associated with the pathogenesis of ARH.

关键词

Keywords

references

冉庄, 陈郁, 谭超, 等. 基于新型住宿方舱的弥散供氧对移居高原人员生理学效应的影响[J]. 第三军医大学学报, 2021, 43(8): 707-714. DOI: 10.16016/j.1000-5404.202010080.

RAN Z, CHEN Y, TAN C, et al . Influence of diffuse oxygen supply on physiological effects in migrants in plateau: astudy based on a new accommodation cabin[J ] . J Third Mil Med Univ, 2021, 43(8): 707-714. DOI: 10.16016/j.1000-5404.202010080.

Cb D, Td S, J S, et al . Hypertension and acute mountain sickness in Himalayan Trekkers in Nepal: An observational cohort study[J ] . Wild Environ Med Wilderness Environ Med, 2020, 31(2): 157-164. DOI: 10.1016/j.wem.2020.01.004

林莹, 张宇清. 高原性高血压的患病率、发病机制及治疗研究进展[J]. 中华高血压杂志, 2020, 28(1): 82-86. DOI: 10.16439/j.cnki.1673-7245.2020.01.025.

LIN Y, ZHANG Y Q. Research progress on the prevalence, pathogenesis and treatment of high primary hypertension[J]. Chin J Hypertens, 2020, 28(1): 82-86. DOI: 10.16439/j.cnki.1673-7245.2020.01.025.

Riley C J, Gavin M. Physiological changes to the cardiovascular system at high altitude and its effects on cardiovascular disease[J]. High Alti Med Biol, 2017, 18(2): 102-113. DOI: 10.1089/ham.2016.0112.

刘鑫源, 罗勇军. 急性高原(山)病诊断标准的演变历程及最新进展[J]. 解放军预防医学杂志, 2019, 37(10): 188-192. DOI: 10.13704/j.cnki.jyyx.2019.10.070.

LIU X Y, LUO Y J. Evolution and recent progress of diagnostic criteria for acute plateau (mountain) disease[J]. J Prev Med Chin PLA, 2019, 37(10): 188-192. DOI: 10.13704/j.cnki.jyyx.2019.10.070.

MINGJI C, ONAKPOYA I J, PERERA R, et al . Relationship between altitude and the prevalence of hypertension in Tibet: a systematic review[J ] . Heart, 2015, 101(13 ): 1054-1060. DOI: 10.1136/heartjnl-2014-307158.

YUE L, FAN Z, SUN L, et al . Prevalence of essential hypertension and its complications among Chinese population at high altitude[J ] . High Alti Med Biol, 2017, 18(2): 140-144. DOI: 10.1089/ham.2016.0078.

HOU Y P, WU J L, TAN C, et al . Sex-based differences in the prevalence of acute mountainsickness: a meta-analysis[J ] . Mil Med Res, 2019, 6(1): 38. DOI: 10.1186/s40779-019-0228-3.

李淑敏, 蒋海强, 齐冬梅, 等. 基于代谢组学技术筛选与血压升高相关的差异性代谢物[J]. 中国比较医学杂志, 2022, 32(6): 23-30. DOI: 10.3969/j.issn.1671-7856.2022.06.004.

LI S M, JIANG H Q, QI D M, et al . Screening of differential metabolites related to elevated blood pressure according to metabolomics technology[J ] . Chin J Comp Med, 2022, 32(6): 23-30. DOI: 10.3969/j.issn.1671-7856.2022.06.004.

LAW W S, HUANG P Y, ONG E S, et al . Metabonomics investigation of human urine after ingestion of green tea with gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry and (1)H NMR spectroscopy[J ] . Rapid Commun Mass Spectrom, 2008, 22(16): 2436-2446. DOI: 10.1002/rcm.3629.

MANTZOURANIS E, KAKARGIA E, KAKARGIAS F, et al . The imp act of high protein diets on cardiovascular outcomes: a systematic review and meta-analysis of prospective cohort studies[J ] . Nutrients, 2023, 15(6): 1372. DOI: 10.3390/nu15061372.

ZHANG X Y, SERGIN I, EVANS T D, et al . High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy[J ] . Nat Metab, 2020, 2(1): 110-125. DOI: 10.1038/s42255-019-0162-4.

ABEBE W, MOZAFFARI M S. Role of taurine in the vasculature: an overview of experimental and human studies[J]. Am J Cardiovasc Dis, 2011, 1(3): 293-311.

MOALI C, BOUCHER J L, SARI M A, et al . Substrate specificity of NO synthases: detailed comparison of L-arginine, homo-L-arginine, their N omega-hydroxy derivatives, and N omega-hydroxynor-L-arginine[J ] . Biochemistry, 1998, 37(29): 10453-10460. DOI: 10.1021/bi980742t.

KOENERS M P, VAN FAASSEN E E, WESSELING S, et al . Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long-term antihypertensive effects[J ] . Hypertension, 2007, 50(6): 1077-1084. DOI: 10.1161/HYPERTENSIONAHA.107.095794.

WANG Y T, LIU H Z, MCKENZIE G, et al . Kynurenine is an endothelium-derived relaxing factor produced duri ng inflammation[J ] . Nat Med, 2010, 16(3): 279-285. DOI: 10.1038/nm.2092.

方宁远, 吕力为, 吕晓希, 等. 中国高尿酸血症相关疾病诊疗多学科专家共识(2023年版)[J]. 中国实用内科杂志, 2023, 43(6): 461-480. DOI: 10.19538/j.nk2023060106.

FANG N Y, LYU L W, LYU X X, et al . China multi-disciplinary expert consensus on diagnosis and treatment of hyperuricemia and related diseases (2023 Edition)[J ] . Chin J Pract Intern Med, 2023, 43(6): 461-480. DOI: 10.19538/j.nk2023060106.

KUWABARA M. Hyperuricemia, cardiovascular disease, and hypertension[J]. Pulse (Basel), 2016, 3(3/4): 242-252. DOI: 10.1159/000443769.

LIN Y T, SALIHOVIC S, FALL T, et al . Global plasma metabolomics to identify potential biomarkers of blood pressure progression[J ] . Arterioscler Thromb Vasc Biol, 2020, 40(8): e227-e237. DOI: 10.1161/ATVBAHA.120.314356.

WANG D D, TOLEDO E, HRUBY A, et al . Plasma ceramides, Mediterranean diet, and incident cardiovascular disease in the PREDIMED trial (prevención con dieta mediterránea)[J ] . Circulation, 2017, 135(21): 2028-2040. DOI: 10.1161/CIRCULATIONAHA.116.024261.

JIANG X C, GOLDBERG I J, PARK T S. Sphingolipids and cardiovascular diseases: lipoprotein metabolism, atherosclerosis and cardiomyopathy[J]. Adv Exp Med Biol, 2011, 721: 19-39. DOI: 10.1007/978-1-4614-0650-1_2.

SPIJKERS L J A, VAN DEN AKKER R F P, JANSSEN B J A, et al . Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide[J ] . PLoS One, 2011, 6(7): e21817. DOI: 10.1371/journal.pone.0021817.

SPIJKERS L J, JANSSEN B J, NELISSEN J, et al . Antihypertensive treatment differentially affects vascular sphingolipid biology in spontaneously hypertensive rats[J ] . PLoS One, 2011, 6(12): e29222. DOI: 10.1371/journal.pone.0029222.

HENNENBERG M, TREBICKA J, SAUERBRUCH T, et al . Mechanisms of extrahepatic vasodilation in portal hypertension[J ] . Gut, 2008, 57(9): 1300-1314. DOI: 10.1136/gut.2007.144584.

LJUBUNCIC P, SAID O, EHRLICH Y, et al . On the in vitro vasoactivity of bile acids[J ] . Br J Pharmacol, 2000, 131(3): 387-398. DOI: 10.1038/sj.bjp.0703554..

KHURANA S, YAMADA M, WESS J, et al . Deoxycholyltaurine-induced vasodilation of rodent aorta is nitric oxide- and muscarinic M(3) receptor-dependent[J ] . Eur J Pharmacol, 2005, 517(1/2): 103-110. DOI: 10.1016/j.ejphar.2005.05.037.

NAKAJIMA T, OKUDA Y, CHISAKI K, et al . Bile acids increase intracellular Ca(2+) concentration and nitric oxide production in vascular endothelial cells[J ] . Br J Pharmacol, 2000, 130(7): 1457-1467. DOI: 10.1038/sj.bjp.0703471.

JADEJA R N, THOUNAOJAM M C, BARTOLI M, et al . Deoxycholylglycine, a conjugated secondary bile acid, reduces vascular tone by attenuating Ca 2+ sensitivity via rho kinase pathway[J ] . Toxicol Appl Pharmacol, 2018, 348: 14-21. DOI: 10.1016/j.taap.2018.04.012..

叶梓, 刘鑫源, 陈郁, 等. 基于血液学参数的急性高原反应潜在预测指标的筛查分析[J]. 重庆医学, 2023, 52(23): 3560-3566. DOI: 10.3969/j.issn.1671-8348.2023.23.007.

YE Z, LIU X Y, CHEN Y, et al . Screening analysis of potential predictors of acute mountain sickness based on hematological parameters[J ] . Chongqing Med, 2023, 52(23): 3560-3566. DOI: 10.3969/j.issn.1671-8348.2023.23.007.

Views

219

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

A metabolomic study of Baihe Zhimu decoction in a rat model of depression

Related Author

Zhirui LIU

Bo YANG

Fang LIU

Yanlei GUO

Peiyuan XIA

Related Institution

No data

⁰