Fig. 4.

Pharmacological inhibition of glucose-6-phosphate dehydrogenase (G6PD) attenuated metabolic reprogramming in lungs of CYP2C44^−/− hypoxic mice. A and B: exposure to hypoxia for 1.5 (orange) to 5 wk (red) of mouse lungs (blue) promotes the activation of the pentose phosphate pathway and accumulation of late Krebs cycle intermediates. This phenotype is rescued by inhibition of G6PD by NEOU (1.5 mg·kg⁻¹·day⁻¹; sc)-treated mice in week 4 (for 1 wk), which also promoted glutathione synthesis and increased the total glutathione pool (reduced + oxidized; C), while decreasing the levels of the hypoxic marker hypoxanthine (C). These pathways were highlighted by unsupervised principal component analysis (PCA; D), which showed a clear rescue by the G6PD inhibition treatment on the metabolic reprogramming induced by hypoxia in mouse lungs. An overview of the main pathways affected by the various treatments is provided in the heat map in E (blue to red = low to high levels of metabolites in that pathway across all replicates). n = 10 in the Normoxia Group; n = 5 in the Hypoxia Group at 1.5 wk; n = 5 in the Hypoxia Group at 5 wk; and n = 5 in the Hypoxia+NEOU Group; males and females (3:2 ratio) were included in all groups. *P < 0.05; **P < 0.01; and ***P < 0.005.