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

磷酸戊糖途径 内科学 心力衰竭 心肌保护 内分泌学 心肌细胞 体内 氧化应激 医学 糖酵解 心功能曲线 下调和上调 谷胱甘肽 新陈代谢 药理学 生物化学 生物 心肌梗塞 生物技术 基因
作者
Lauriane Y. M. Michel,Hrag Esfahani,Delphine De Mulder,Roxane Verdoy,Jérôme Ambroise,Véronique Roelants,Brigitte 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 Rosiers,Jean‐Luc Balligand
出处
期刊:Circulation [Ovid Technologies (Wolters Kluwer)]
标识
DOI:10.1161/circulationaha.124.067876
摘要

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