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Integration of metabolomics and transcriptomic expression profiling discloses pivotal role of arachidonic acid metabolism pathway in response to acute hypoxia exposure

ABSTRACT: Background: Arachidonic acid (AA) metabolism pathway is dominant in metabolic programming after hypoxia exposure, but its biological function is disputed and require in-depth studies. In this research, we aimed at integrating plasma metabolomics and transcriptomics approaches to systematically explore its roles in response to acute hypoxia based on model of acute high-altitude exposure. Methods: Blood samples were taken from 53 enrolled subjects before and after their exposure to high altitude. Ultra-performance liquid chromatography- quadrupole time-of-flight mass spectrometry and RNA sequencing were performed to acquire corresponding metabolomic and transcriptomic profiling along with hypoxia exposure, separately. Influential modules comprising essential metabolites and genes were identified by weighted gene co-expression network analysis (WGCNA) after integrating metabolic information with phenotypic and transcriptomic datasets, respectively. Results: Enrolled individuals showed significant alterations in heart rate, SpO2, hemoglobin and Lake Louise Score (LLS) in response to hypoxia. Metabolomics profiling demonstrated that AA metabolism pathway was remarkable in these metabolic alterations. Integrated analysis of metabolomic and transcriptomic data revealed that increasing AA metabolism pathway might count for gas transport incapacitation and disorders in hemoglobin metabolism under hypoxia stimuli. Moreover, identified in further analysis and another cohort, excessively elevated AA metabolism pathway was involved in poor response to hypoxia. Conclusion: Our study, for the first time, constructed the maps of AA metabolism pathway in response to hypoxia; and revealed the crosstalk between phenotypic variation to hypoxia and AA metabolism pathway. These findings will not only advanced pathophysiological mechanisms for acute hypoxic diseases, but provided new insights into critical roles of AA metabolism pathway in development and prevention of these diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103940 | GEO | 2018/03/09

REPOSITORIES: GEO

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Project description:Exposure to hypoxia disrupts energy metabolism and induces inflammation. However, the pathways and mechanisms underlying energy metabolism disorders caused by hypoxic conditions remain unclear. In this study, we constructed a hypoxic animal model and applied transcriptomic and non-targeted metabolomics techniques to further investigate the pathways and mechanisms of hypoxia exposure that disrupt energy metabolism. Transcriptome results showed that 3007 genes were significantly differentially expressed under hypoxic exposure, and Gene Ontology (GO) annotation analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes (DEGs) were mainly involved in energy metabolism and were significantly enriched in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathway. Differential genes in the TCA cycle (IDH3A, SUCLA2, and MDH2) and OXPHOS pathway (NDUFA3, NDUFS7, UQCRC1, CYC1, and UQCRFS1) were validated using mRNA and protein expression, and the results showed downregulation. The results of non-targeted metabolomics showed that 365 significant differential metabolites were identified under plateau hypoxia stress. KEGG enrichment analysis showed that the differential metabolites were mainly enriched in metabolic processes, such as energy metabolism, nucleotide metabolism, and amino acid metabolism. Hypoxia exposure disrupted the TCA cycle and reduced the synthesis of amino acids and nucleotides by decreasing the concentrations of cis-aconitate, α-ketoglutarate, NADH, NADPH, most amino acids, purines, and pyrimidines. Bioinformatics analysis was used to identify inflammatory genes related to hypoxia exposure, and some inflammatory genes were selected for verification. We found that the mRNA and protein expression levels of IL1B, IL12B, S100A8, and S100A9 in kidney tissues were upregulated under hypoxic exposure. Our results suggest that hypoxia exposure inhibits the TCA cycle and OXPHOS signalling pathway by inhibiting IDH3A, SUCLA2, MDH2, NDUFFA3, NDUFS7, UQCRC1, CYC1, and UQCRFS1, thereby suppressing energy metabolism, inducing amino acid and nucleotide deficiency, and promoting inflammation, ultimately leading to kidney damage.

Project description:Background: Responses to hypoxia have been investigated in many species; however, comparative study between conspecific geographical populations in different altitude regions is rare, especially for invertebrates . The migratory locust, Locusta migratoria, is widely distributed both on high-altitude Tibetan Plateau (TP) and on low-altitude North China Plain (NP). TP locusts have inhabited Tibetan Plateau since Quaternary glaciations events and thus probably have evolved superior capacity to deal with hypoxia. Results: Here we compared the hypoxic responses of TP and NP locusts from morphological, behavioral and physiological perspectives. We found that TP locusts were more tolerant of extreme hypoxia than NP locusts, with a lower proportion exhibiting stupor, a faster recovery time, and higher respiration rates. We compared the transcriptional profiles of field TP and NP locusts and found that their differences were possibly attributed to a combination of multiple factors, e.g. oxygen, UV radiation, temperature and nutrition. To evaluate why TP locusts respond to extreme hypoxia differently from NP locusts, we subjected them to extreme hypoxia and compared their transcriptional responses. We found that the aerobic metabolism was more active in TP locusts than in NP locusts. RNAi disruption of PDHE1b, an entry gene from glycolysis to TCA cycle, increased the ratio of stupor in Tibetan locusts and decreased the ATP content of Tibetan locusts in hypoxia, confirming the significant importance of this metabolic branch for TP locusts to conquer hypoxia. Conclusions: Here we show that TP locusts are better tolerant of hypoxia than NP locusts and the better capacity to modulate primary metabolism in TP locusts contributes to their superior tolerance of hypoxia compared to NP locusts. FIELD POPULATION: TP locusts vs. NP locusts;direct comparison on 6 separate microarrays; each microarray compares one biological replicate; each biological replicate contains 10 individuals. LAB POPULATION: hypoxia-treated TP locusts vs TP locusts in normoxia; hypoxia-treated NP locusts vs NP locusts in normoxia; direct comparison on 6 separate microarrays; each microarray compares one biological replicate; each biological replicate contains 10 individuals.

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Integration of metabolomics and transcriptomic expression profiling discloses pivotal role of arachidonic acid metabolism pathway in response to acute hypoxia exposure

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