1. Academic Validation
  2. Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside

Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside

  • Basic Res Cardiol. 2024 Mar 25. doi: 10.1007/s00395-024-01042-4.
Y Xiao # 1 2 3 Q Wang # 1 2 H Zhang 1 2 R Nederlof 4 D Bakker 1 2 B A Siadari 1 M W Wesselink 1 B Preckel 1 2 N C Weber 1 2 M W Hollmann 1 2 B V Schomakers 5 6 M van Weeghel 2 5 6 7 C J Zuurbier 8 9
Affiliations

Affiliations

  • 1 Amsterdam UMC, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
  • 2 Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands.
  • 3 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
  • 4 Institut für Herz- und Kreislaufphysiologie, Medizinische fakultät und Universitätsklinikum Düsseldorf, Heinrich- Heine- Universität Düsseldorf, Düsseldorf, Germany.
  • 5 Laboratory Genetic Metabolic Diseases, Location Academic Medical Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
  • 6 Core Facility Metabolomics, Location Academic Medical Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.
  • 7 Amsterdam Gastroenterology Endocrinology and Metabolism Institute, Amsterdam, The Netherlands.
  • 8 Amsterdam UMC, Laboratory of Experimental Intensive Care and Anesthesiology, Department of Anesthesiology, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.j.zuurbier@amsterdamumc.nl.
  • 9 Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands. c.j.zuurbier@amsterdamumc.nl.
  • # Contributed equally.
Abstract

Decreased nicotinamide adenine dinucleotide (NAD+) levels contribute to various pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion injury (IRI). Nicotinamide riboside (NR) has emerged as a promising therapeutic NAD+ precursor due to efficient NAD+ elevation and was recently shown to be the only agent able to reduce cardiac IRI in models employing clinically relevant anesthesia. However, through which metabolic pathway(s) NR mediates IRI protection remains unknown. Furthermore, the influence of Insulin, a known modulator of cardioprotective efficacy, on the protective effects of NR has not been investigated. Here, we used the isolated mouse heart allowing cardiac metabolic control to investigate: (1) whether NR can protect the isolated heart against IRI, (2) the metabolic pathways underlying NR-mediated protection, and (3) whether Insulin abrogates NR protection. NR protection against cardiac IRI and effects on metabolic pathways employing metabolomics for determination of changes in metabolic intermediates, and 13C-glucose fluxomics for determination of metabolic pathway activities (glycolysis, pentose phosphate pathway (PPP) and mitochondrial/tricarboxylic acid cycle (TCA cycle) activities), were examined in isolated C57BL/6N mouse hearts perfused with either (a) glucose + fatty acids (FA) ("mild glycolysis group"), (b) lactate + pyruvate + FA ("no glycolysis group"), or (c) glucose + FA + Insulin ("high glycolysis group"). NR increased cardiac NAD+ in all three metabolic groups. In glucose + FA perfused hearts, NR reduced IR injury, increased glycolytic intermediate phosphoenolpyruvate (PEP), TCA intermediate succinate and PPP intermediates ribose-5P (R5P) / sedoheptulose-7P (S7P), and was associated with activated glycolysis, without changes in TCA cycle or PPP activities. In the "no glycolysis" hearts, NR protection was lost, whereas NR still increased S7P. In the Insulin hearts, glycolysis was largely accelerated, and NR protection abrogated. NR still increased PPP intermediates, with now high 13C-labeling of S7P, but NR was unable to increase metabolic pathway activities, including glycolysis. Protection by NR against IRI is only present in hearts with low glycolysis, and is associated with activation of glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. The data suggest that NR's acute cardioprotective effects are mediated through glycolysis activation and are lost in the presence of Insulin because of already elevated glycolysis.

Keywords

Glycolysis; IR injury; Insulin; NAD+; PPP pathway.

Figures
Products