NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway

Anna Zoccarato; Ioannis Smyrnias; Christina M Reumiller; Anne D Hafstad; Mei Chong; Daniel A Richards; Celio X C Santos; Asjad Visnagri; Sharwari Verma; Daniel I Bromage; Min Zhang; Xiaohong Zhang; Greta Sawyer; Richard Thompson; Ajay M Shah

doi:10.1093/cvr/cvae250

NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway

Cardiovasc Res. 2024 Dec 6:cvae250. doi: 10.1093/cvr/cvae250. Online ahead of print.

Authors

Anna Zoccarato¹, Ioannis Smyrnias^{1

2}, Christina M Reumiller¹, Anne D Hafstad^{1

3}, Mei Chong¹, Daniel A Richards¹, Celio X C Santos¹, Asjad Visnagri¹, Sharwari Verma¹, Daniel I Bromage¹, Min Zhang¹, Xiaohong Zhang¹, Greta Sawyer¹, Richard Thompson¹, Ajay M Shah¹

Affiliations

¹ School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK.
² Comparative Biomedical Sciences, University of Surrey, Guildford, UK.
³ Cardiovascular Research Group, Department of Medical Biology, UiT, The Arctic University of Norway, Tromsø, Norway.

PMID: 39657243
DOI: 10.1093/cvr/cvae250

Abstract

Aims: The transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 enhances resistance of mouse hearts to chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. Here, we investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress.

Methods and results: Cardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 redirected glucose metabolism towards the pentose phosphate pathway (PPP), a branch pathway of glycolysis, and mitigated pressure overload-induced cardiomyocyte death and cardiac dysfunction. Activation of NRF2 also protected against myocardial infarction-induced DNA damage in remote myocardium and cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP.

Conclusions: These results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby generating NADPH and providing nucleotides to prevent stress-induced DNA damage and cardiac dysfunction.