NR: A Cardioprotective Booster via Glycolysis Activation in Low Insulin Settings
Introduction
Nicotinamide adenine dinucleotide (NAD+) metabolism is essential for maintaining normal physiological activities, and the decreased NAD+ level is related to various pathologies such as cardiac diseases and ischemia-reperfusion (IR) Injury. Nicotinamide riboside (NR) now appears as optimal NAD+ precursor to mitigate acute cardiac IR injury. Notably, glycolysis activation may be one of the metabolic pathways underlying NR-mediated cardioprotection, and insulin can abrogate this protection.The merits of NR in protecting hearts
By virtue of its high bioavailability, its safety in healthy adults or obese patients, and its superiority in efficient NAD+ elevation in humans as compared to other agents, NR has emerged as a leading NAD+ precursor candidate. Up till now, NR has been the only compound to retain cardioprotection in an in vivo IR model with clinically relevant anesthesia.About glycolysis
Glycolysis is a metabolic process that allows organisms to obtain energy from glucose under aerobic and anaerobic conditions. During this process, glucose (C6H12O6) can converted into pyruvate (CH3COCOO + H). The released free energy is used to form the high-energy compounds adenosine triphosphate (ATP) and the reduced form of nicotinamide adenine dinucleotide (NADH). Glycolysis is the first step in the process of sugar metabolism in all living cells, which can be regulated to accommodate different metabolic needs.
NR-mediated cardio-protection in relation to glycolysis and insulin
NR treatment reduces IR-induced cardiac injury in the mouse heart. This protection is associated with glycolysis activation and abrogated in the presence of insulin. Concretely, NR increases NAD+ level, intermediates of glycolysis, pentose phosphate pathway (PPP) and tricarboxylic acid (TCA) cycle, and activates glycolysis in low glycolysis hearts (perfusion of glucose and fatty acid). When glycolysis is already fully activated by high plasma levels of insulin, NR’s protective effect against cardiac IR injury will be diminished or even absent.
Conclusion
The perioperative metabolic condition (e.g. fasting, low insulin versus non-fasting high insulin conditions) likely dictates the efficacy of NR treatment as therapy against cardiac IR injury. NR may especially offer protection through activation of glycolysis in conditions of low insulin, and its protective potential can diminish in the presence of insulin.Reference
[1] Xiao Y, Phelp P, Wang Q, et al. Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol. Front Cardiovasc Med. 2021;8:712478. Published 2021 Aug 30. doi:10.3389/fcvm.2021.712478[2] Xiao Y, Wang Q, Zhang H, et al. Insulin and glycolysis dependency of cardioprotection by nicotinamide riboside. Basic Res Cardiol. 2024;119(3):403-418. doi:10.1007/s00395-024-01042-4
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