title: Metabolic fingerprint of ischaemic cardioprotection: importance of the malate-aspartate shuttle.
abstract: The convergence of cardioprotective intracellular signalling pathways to modulate mitochondrial function as an end-target of cytoprotective stimuli is well described. However, our understanding of whether the complementary changes in mitochondrial energy metabolism are secondary responses or inherent mechanisms of ischaemic cardioprotection remains incomplete. In the heart, the malate-aspartate shuttle (MAS) constitutes the primary metabolic pathway for transfer of reducing equivalents from the cytosol into the mitochondria for oxidation. The flux of MAS is tightly linked to the flux of the tricarboxylic acid cycle and the electron transport chain, partly by the amino acid l-glutamate. In addition, emerging evidence suggests the MAS is an important regulator of cytosolic and mitochondrial calcium homeostasis. In the isolated rat heart, inhibition of MAS during ischaemia and early reperfusion by the aminotransferase inhibitor aminooxyacetate induces infarct limitation, improves haemodynamic responses, and modulates glucose metabolism, analogous to effects observed in classical ischaemic preconditioning. On the basis of these findings, the mechanisms through which MAS preserves mitochondrial function and cell survival are reviewed. We conclude that the available evidence is supportive of a down-regulation of mitochondrial respiration during lethal ischaemia with a gradual 'wake-up' during reperfusion as a pivotal feature of ischaemic cardioprotection. Finally, comments on modulating myocardial energy metabolism by the cardioprotective amino acids glutamate and glutamine are given.
authors.affiliation: Department of Cardiology, Skejby Hospital, Aarhus University Hospital, Brendstrupgaardsvej 100, Aarhus N, Denmark. toftegaard@ki.au.dk
authors.forename: Torsten Toftegaard
authors.initials: TT
authors.lastname: Nielsen
authors.forename: Nicolaj Brejnholt
authors.initials: NB
authors.lastname: Støttrup
authors.forename: Bo
authors.initials: B
authors.lastname: Løfgren
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008293:Malates / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
chemical_list: D008293:Malates; D001224:Aspartic Acid; C030298:malic acid; D002118:Calcium