Metabolomic profiling of the heart during acute ischemic preconditioning reveals a role for SIRT1 in rapid cardioprotective metabolic adaptation

J Mol Cell Cardiol. 2015 Nov;88:64-72. doi: 10.1016/j.yjmcc.2015.09.008. Epub 2015 Sep 24.

Abstract

Ischemic preconditioning (IPC) protects tissues such as the heart from prolonged ischemia-reperfusion (IR) injury. We previously showed that the lysine deacetylase SIRT1 is required for acute IPC, and has numerous metabolic targets. While it is known that metabolism is altered during IPC, the underlying metabolic regulatory mechanisms are unknown, including the relative importance of SIRT1. Thus, we sought to test the hypothesis that some of the metabolic adaptations that occur in IPC may require SIRT1 as a regulatory mediator. Using both ex-vivo-perfused and in-vivo mouse hearts, LC-MS/MS based metabolomics and (13)C-labeled substrate tracing, we found that acute IPC altered several metabolic pathways including: (i) stimulation of glycolysis, (ii) increased synthesis of glycogen and several amino acids, (iii) increased reduced glutathione levels, (iv) elevation in the oncometabolite 2-hydroxyglutarate, and (v) inhibition of fatty-acid dependent respiration. The majority (83%) of metabolic alterations induced by IPC were ablated when SIRT1 was acutely inhibited with splitomicin, and a principal component analysis revealed that metabolic changes in response to IPC were fundamentally different in nature when SIRT1 was inhibited. Furthermore, the protective benefit of IPC was abrogated by eliminating glucose from perfusion media while sustaining normal cardiac function by burning fat, thus indicating that glucose dependency is required for acute IPC. Together, these data suggest that SIRT1 signaling is required for rapid cardioprotective metabolic adaptation in acute IPC.

Keywords: Fatty acids; Glucose; Ischemia; Preconditioning; Reperfusion; Sirtuin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptation, Physiological
  • Amino Acids / biosynthesis
  • Animals
  • Cell Respiration
  • Fatty Acids / metabolism
  • Gene Expression
  • Glutarates / metabolism
  • Glutathione / biosynthesis
  • Glycogen / biosynthesis
  • Glycolysis / genetics
  • Ischemic Preconditioning, Myocardial*
  • Metabolome*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardial Reperfusion Injury / pathology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Naphthalenes / pharmacology
  • Organ Culture Techniques
  • Principal Component Analysis
  • Pyrones / pharmacology
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics*
  • Sirtuin 1 / metabolism

Substances

  • Amino Acids
  • Fatty Acids
  • Glutarates
  • Naphthalenes
  • Pyrones
  • alpha-hydroxyglutarate
  • splitomicin
  • Glycogen
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Glutathione