An NRF2/β3-Adrenoreceptor Axis Drives a Sustained Antioxidant and Metabolic Rewiring Through the Pentose-Phosphate Pathway to Alleviate Cardiac Stress

• DOI: 10.1161/circulationaha.124.067876
• Publication Date: 2025-03-12T09:00:29Z
• Authors: Lauriane Y.M. Michel; Hrag Esfahani; Delphine De Mulder; Roxane Verdoy; Jérôme Ambroise; Véronique Roelants; Bertrand Bouchard; Nathalie Fabian; Jérôme Savary; Joseph P. Dewulf; Thomas Doumont; Caroline Bouzin; Vincent Haufroid; Joost J.F.P. Luiken; Miranda Nabben; Michael L. Singleton; Luc Bertrand; Matthieu Ruiz; Christine Des Ros...; Jean-Luc Balligand
• Keywords: Cardioprotection

BACKGROUND: Cardiac β3-adrenergic receptors (ARs) are upregulated in diseased hearts and mediate antithetic effects to those of β1AR β2AR. β3AR agonists were recently shown protect against myocardial remodeling preclinical studies improve systolic function patients with severe heart failure. However, the underlying mechanisms remain elusive. METHODS: To dissect functional, transcriptional, metabolic effects, isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression human ADRB3 transgene (β3AR-Tg) subjected transverse aortic constriction assessed echocardiography, RNA sequencing, positron emission tomography scan, metabolomics, flux analysis. Subsequently, signaling pathways further investigated vivo β3AR-Tg ex neonatal rat adenovirally infected express neurohormonal stress. These results complemented an analysis single-nucleus RNA-sequencing data cardiac RESULTS: Compared wild-type littermates, protected hypertrophy after transaortic constriction, was preserved. β3AR-expressing displayed enhanced glucose uptake under stress absence increased lactate levels. Instead, metabolomic analyses stressed revealed increase intermediates pentose-phosphate pathway β3AR-Tg, alternative route utilization, paralleled transcript levels NADPH-producing rate-limiting enzymes pathway, without fueling hexosamine metabolism. The ensuing content NADPH reduced glutathione decreased myocyte oxidant stress, whereas downstream oxidative metabolism by oxygen consumption preserved higher oxidation compared wild type, together mitochondrial biogenesis. Unbiased transcriptomics identified NRF2 (NFE2L2) as upstream transcription factor that functionally verified myocytes, where its translocation nuclear activity dependent on activation nitric oxide synthase production through S-nitrosation NRF2-negative regulator Keap1. CONCLUSIONS: Moderate β3AR, at observed myocardium, exerts antioxidant Keap1, thereby preserving metabolism, function, integrity pathophysiological