Arachidonic Acid Metabolism Pathway Is Not Only Dominant in Metabolic Modulation but Associated With Phenotypic Variation After Acute Hypoxia Exposure

Chang Liu, Bao Liu, Lu Liu, Er-Long Zhang, Bind-da Sun, Gang Xu, Jian Chen, Yu-qi Gao

Background: The modulation of arachidonic acid (AA) metabolism pathway is identified in metabolic alterations after hypoxia exposure, but its biological function is controversial. We aimed at integrating plasma metabolomic and transcriptomic approaches to systematically explore the roles of the AA metabolism pathway in response to acute hypoxia using an acute mountain sickness (AMS) model. Methods: Blood samples were obtained from 53 enrolled subjects before and after exposure to high altitude. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and RNA sequencing were separately performed for metabolomic and transcriptomic profiling, respectively. 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 subjects exhibited diverse response manners to hypoxia. Combined with obviously altered heart rate, oxygen saturation, hemoglobin, and Lake Louise Score (LLS), metabolomic profiling detected that 36 metabolites were highly related to clinical features in hypoxia responses, out of which 27 were upregulated and nine were downregulated, and could be mapped to AA metabolism pathway significantly. Integrated analysis of metabolomic and transcriptomic data revealed that these dominant molecules showed remarkable association with genes in gas transport incapacitation and disorders of hemoglobin metabolism pathways, such as ALAS2, HEMGN. After detailed description of AA metabolism pathway, we found that the molecules of 15-d-PGJ2, PGA2, PGE2, 12-O-3-OH-LTB4, LTD4, LTE4 were significantly up-regulated after hypoxia stimuli, and increased in those with poor response manner to hypoxia particularly. Further analysis in another cohort showed that genes in AA metabolism pathway such as PTGES, PTGS1, GGT1, TBAS1 et al. were excessively elevated in subjects in maladaptation to hypoxia. Conclusion: This is the first study to construct the map of AA metabolism pathway in response to hypoxia and reveal the crosstalk between phenotypic variation under hypoxia and the AA metabolism pathway. These findings may improve our understanding of the advanced pathophysiological mechanisms in acute hypoxic diseases and provide new insights into critical roles of the AA metabolism pathway in the development and prevention of these diseases.