Heart failure & cardiomyopathies
An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress
Authors' conclusion
Moderate expression of cardiac β3AR, at levels observed in human cardiac myocardium, exerts metabolic and antioxidant effects through activation of the pentose-phosphate pathway and NRF2 pathway through S-nitrosation of Keap1, thereby preserving myocardial oxidative metabolism, function, and integrity under pathophysiological stress.
Study context
- Population
- Mice subjected to transverse aortic constriction; neonatal rat ventricular myocytes under neurohormonal stress; human HF cardiac myocytes
- Comparison
- β3AR-Tg vs wild-type littermates
Methodological detailstransgenic mouse model, transverse aortic constriction, neonatal rat ventricular myocytes, human single-nucleus RNA-sequencing data
- Transgenic mouse model
- Transverse aortic constriction
- Neonatal rat ventricular myocytes
- Human single-nucleus RNA-sequencing data
Main finding
As reported in the abstract
- β3AR-Tg protected from hypertrophy after transaortic constriction, systolic function preserved, vs wild type
- Enhanced myocardial glucose uptake under stress without increased lactate
- Increased pentose-phosphate pathway intermediates and transcripts of NADPH-producing and rate-limiting enzymes, without fueling hexosamine metabolism
- Increased NADPH and reduced glutathione; decreased myocyte oxidant stress
- Oxygen consumption preserved with higher glucose oxidation and increased mitochondrial biogenesis vs wild type after transaortic constriction
- NRF2 (NFE2L2) identified as upstream transcription factor; its translocation and nuclear activity dependent on β3AR activation of nitric oxide synthase and S-nitrosation of Keap1
Original publication
An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress. Circulation. Published 12 March 2025. doi:10.
Summarised from the published abstract; every number is checked against it