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HIF-1? is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium.


ABSTRACT: Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1? (HIF-1?), downstream of NAD(P)H oxidase-4 (NOX4)-derived reactive oxygen species (ROS). HIF-1? increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1?, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow-induced metabolic reprogramming and inflammation in ECs.

SUBMITTER: Wu D 

PROVIDER: S-EPMC5495571 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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<i>HIF-1α</i> is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium.

Wu David D   Huang Ru-Ting RT   Hamanaka Robert B RB   Krause Matt M   Oh Myung-Jin MJ   Kuo Cheng-Hsiang CH   Nigdelioglu Recep R   Meliton Angelo Y AY   Witt Leah L   Dai Guohao G   Civelek Mete M   Prabhakar Nanduri R NR   Fang Yun Y   Mutlu Gökhan M GM  

eLife 20170530


Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced  ...[more]

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