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2018 ; 9
(ä): 236
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Arachidonic Acid Metabolism Pathway Is Not Only Dominant in Metabolic Modulation
but Associated With Phenotypic Variation After Acute Hypoxia Exposure
#MMPMID29615930
Liu C
; Liu B
; Liu L
; Zhang EL
; Sun BD
; Xu G
; Chen J
; Gao YQ
Front Physiol
2018[]; 9
(ä): 236
PMID29615930
show ga
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.