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Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia/reperfusion injury in the heart

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. Using a genetically encoded fluorescent indicator, we found that exercise increased cytosolic, but not mitochondrial, NADPH levels in cardiomyocytes. This effect was mediated by activation of pentose phosphate pathway (PPP). Downregulation of G6PD expression through knocking down transcription factor SP1 or G6PD itself, or depletion of cytosolic NADPH blocked exercise-induced heart hypertrophy. NADPH promoted cardiomyocyte growth through inhibiting HDAC3/C/EBPβ pathways. Moreover, exercise suppressed acute I/R injury and preserved heart function 4 weeks after I/R by mediating G6PD/NADPH pathway. Among 310 Tibetan compounds, lyciumspermidine-0527, a new spermidine derivative, directly activated G6PD, elevated intracellular NADPH levels, promoted cardiomyocytes growth and alleviated I/R injury. PPP-derived NADPH is a critical metabolic checkpoint that regulates exercise-induced physiological cardiomyocyte growth and protects against I/R-induced heart injury.

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

PROVIDER: MTBLS14090 | MetaboLights | 2026-03-22

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14090_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS14090_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14090_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS14090_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Here, we show that production of cardiomyocyte NADPH (nicotinamide adenine dinucleotide phosphate), a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with cardiac cell death, fibrosis, and cardiomyopathy. We report that the pentose phosphate pathway (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two major NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced in the heart by pressure overload. We identify ATF4 (activating transcriptional factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistent with this, joint pathway analysis (JPA) of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in cardiomyocytes in culture leads to a significant increase in NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression in vitro strongly augments metabolic flux within these two pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of pressure overload and accelerates the development of heart failure, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Taken together, our findings reveal that ATF4 plays a critical role in cardiac homeostasis under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

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Pentose phosphate pathway-derived NADPH facilitates physiological hypertrophy and alleviates ischemia/reperfusion injury in the heart

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