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The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in neonates.

ABSTRACT: Dysmorphic pulmonary vascular growth and abnormal endothelial cell (EC) proliferation are paradoxically observed in premature infants with bronchopulmonary dysplasia (BPD), despite vascular pruning. The pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis, generates NADPH as a reducing equivalent and ribose 5-phosphate for nucleotide synthesis. It is unknown whether hyperoxia, a known mediator of BPD in rodent models, alters glycolysis and the PPP in lung ECs. We hypothesized that hyperoxia increases glycolysis and the PPP, resulting in abnormal EC proliferation and dysmorphic angiogenesis in neonatal mice. To test this hypothesis, lung ECs and newborn mice were exposed to hyperoxia and allowed to recover in air. Hyperoxia increased glycolysis and the PPP. Increased PPP, but not glycolysis, caused hyperoxia-induced abnormal EC proliferation. Blocking the PPP reduced hyperoxia-induced glucose-derived deoxynucleotide synthesis in cultured ECs. In neonatal mice, hyperoxia-induced abnormal EC proliferation, dysmorphic angiogenesis, and alveolar simplification were augmented by nanoparticle-mediated endothelial overexpression of phosphogluconate dehydrogenase, the second enzyme in the PPP. These effects were attenuated by inhibitors of the PPP. Neonatal hyperoxia augments the PPP, causing abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification. These observations provide mechanisms and potential metabolic targets to prevent BPD-associated vascular dysgenesis.

SUBMITTER: Gong J

PROVIDER: S-EPMC8021105 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Oxidative pentose phosphate pathway controls vascular mural cell coverage by regulating extracellular matrix composition.

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2021-07-27 | PXD023550 | Pride

The pentose phosphate pathway regulates the circadian clock

Project description:The circadian clock is a ubiquitous timekeeping system that organizes the behavior and physiology of organisms over the day and night. The clockwork orchestrates a multitude of metabolic processes as illustrated by previous global transcriptomics and proteomics studies, and the existence of daily rhythms of reduction and oxidation (redox) in a range of diverse species. However, the reciprocal question of whether metabolism can alter the clockwork remains largely unaddressed. Here we identify the pentose phosphate pathway (PPP), a critical source of cellular reducing power in the form of NADPH, as an important modulator of circadian oscillations. We show that genetic and pharmacologic inhibition of the PPP perturbs circadian gene expression and metabolic rhythms in human cells. Pharmacologic inhibition of the PPP caused similar effects in mouse tissues, and altered the pattern of rhythmic behavior in Drosophila. These manipulations also altered genome wide DNA-binding activity of the circadian transcription factors BMAL1 and CLOCK through a mechanism likely involving the redox-sensitive histone acetyltransferase p300. Thus, disruption of the PPP regulates circadian rhythms via modulation of NADPH metabolism, highlighting redox reactions as a novel connector of metabolic cycles and transcriptional oscillations in nucleated cells.

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