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Metabolomic data related to the alleviation of cardiac ischemia/reperfusion injury by NADPH derived from pentose phosphate pathway

ABSTRACT:

Exercise promotes physiological cardiomyocyte growth and protects against ischemia/reperfusion (I/R) injury in the heart. The molecular mechanism by which exercise benefits cardiac metabolism and function remains largely unknown. Exercise (swimming or treadmill)-induced physiological hypertrophy models were established in mice. Pentose phosphate pathway (PPP) flux was analyzed by 1,2-13C2 glucose stable isotope tracing. In vitro and in vivo manipulations of glucose-6-phosphate dehydrogenase (G6PD) and NADPH were conducted by using lentivirus- and adeno-associated virus-mediated gene transfer, respectively. Myocardial I/R injury model was established in adult mice. Genetically encoded fluorescent indicators (iNap, roGFP, and Hyper) were used to monitor compartmentalized redox and reactive oxygen species (ROS) in neonatal cardiomyocytes during oxygen glucose deprivation/reperfusion (OGD/R). An iNap biosensor-based high-throughput screen was conducted to identify new agents that elevate NADPH levels in cardiomyocytes.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - HILIC, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS14272 | MetaboLights | 2026-05-14

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14272_LC-MS_negative_reverse-phase_metabolite_profiling-1.txt	Txt
	a_MTBLS14272_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS14272_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	a_MTBLS14272_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Project description:Lung ischemia-reperfusion (I/R) injury is a common clinical pathology associated with high mortality. The pathophysiology of lung I/R injury involves ferroptosis and elevated protein O-GlcNAcylation levels, while the effect of O-GlcNAcylation on lung I/R injury remains unclear. This research aimed to explore the effect of O-GlcNAcylation on reducing ferroptosis in pulmonary epithelial cells caused by I/R. First, we identified O-GlcNAc transferase 1 (Ogt1) as a differentially expressed gene in lung epithelial cells of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, using single-cell sequencing, and Gene Ontology analysis (GO analysis) revealed the enrichment of the ferroptosis process. We found a time-dependent dynamic alteration in lung O-GlcNAcylation during I/R injury. Proteomics analysis identified the differentially expressed proteins enriched in ferroptosis and multiple redox-related pathways based on KEGG annotation. Thus, we generated Ogt1-conditional knockout mice and found that Ogt1 deficiency aggravated ferroptosis, as evidenced by lipid reactive oxygen species (lipid ROS), malondialdehyde (MDA), Fe2+, as well as alterations in critical protein expression glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Consistently, we found that elevated O-GlcNAcylation inhibited ferroptosis sensitivity in hypoxia/reoxygenation (H/R) injury-induced TC-1 cells via O-GlcNAcylated NF-E2-related factor-2 (Nrf2). Furthermore, both the chromatin immunoprecipitation (ChIP) assay and the dual-luciferase reporter assay indicated that Nrf2 could bind with translation start site (TSS) of glucose-6-phosphate dehydrogenase (G6PDH) and promote its transcriptional activity. As an important rate-limiting enzyme in the pentose phosphate pathway (PPP), elevated G6PDH provided a mass of nicotinamide adenine dinucleotide phosphate (NADPH) to improve the redox state of glutathione (GSH) and eventually led to ferroptosis resistance. Rescue experiments proved that Nrf2 knockdown or Nrf2-T334A (O-GlcNAcylation site) mutation abolished the protective effect of ferroptosis resistance. In summary, we revealed that O-GlcNAcylation could protect against I/R lung injury by reducing ferroptosis sensitivity via the Nrf2/G6PDH pathway. Our work will provide a new basis for clinical therapeutic strategies for pulmonary ischemia-reperfusion-induced acute lung injury.

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Metabolomic data related to the alleviation of cardiac ischemia/reperfusion injury by NADPH derived from pentose phosphate pathway

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