title: Inhibition of the malate-aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection.
abstract: OBJECTIVE
  Preserved mitochondrial function is essential for protection against ischaemia-reperfusion (IR) injury. The malate-aspartate (MA) shuttle constitutes the principal pathway for transport of reducing cytosolic equivalents for mitochondrial oxidation. We hypothesized that a transient shut-down of the MA-shuttle by aminooxyacetate (AOA) during ischaemia and early reperfusion modulates IR injury by mechanisms comparable to ischaemic preconditioning (IPC).
  
  
  RESULTS
  Isolated perfused rat hearts exposed to 40 min global no-flow ischaemia were studied in: (i) control, (ii) pre-ischaemic AOA (0.1 mM), (iii) IPC, and (iv) AOA+IPC hearts. IR injury was evaluated by infarct size and haemodynamic recovery. Tracer-estimated glucose oxidation and metabolic changes in glycogen, lactate, pyruvate, tricarboxylic acid (TCA) cycle intermediates, and ATP degradation products were measured. The effects of AOA on complex I respiration and reactive oxygen species (ROS) production were examined in isolated rabbit mitochondria. Treatment with AOA, IPC, or AOA+IPC induced significant infarct reduction; 28 ± 6, 30 ± 3, and 18 ± 1%, respectively, vs. 52 ± 5% of left ventricular (LV) mass for control (P < 0.01 for all). LV-developed pressure improved to 60 ± 3, 63 ± 5 and 53 ± 4 vs. 31 ± 5 mmHg (P < 0.01 for all) after 2 h reperfusion. Pre-ischaemic AOA administration inhibited glycolysis and increased glucose oxidation during post-ischaemic reperfusion similar to IPC, and suppressed complex I respiration and ROS production in the non-ischaemic heart. Changes in lactate, pyruvate, TCA intermediates, and ATP end products suggested an AOA inhibition of the MA-shuttle during late ischaemia and early reperfusion.
  
  
  CONCLUSIONS
  Inhibition of the MA-shuttle during ischaemia and early reperfusion is proposed as a mechanism to reduce IR injury.
authors.affiliation: Department of Cardiology, Skejby Hospital, Aarhus University Hospital Skejby, Brendstrupgaardsvej 100, DK-8200 Aarhus, Denmark.
authors.forename: Nicolaj Brejnholt
authors.initials: NB
authors.lastname: Støttrup
authors.forename: Bo
authors.initials: B
authors.lastname: Løfgren
authors.forename: Rune Dupont
authors.initials: RD
authors.lastname: Birkler
authors.forename: Jan Møller
authors.initials: JM
authors.lastname: Nielsen
authors.forename: Lixing
authors.initials: L
authors.lastname: Wang
authors.forename: Christopher Anthony
authors.initials: CA
authors.lastname: Caldarone
authors.forename: Steen Buus
authors.initials: SB
authors.lastname: Kristiansen
authors.forename: Hussain
authors.initials: H
authors.lastname: Contractor
authors.forename: Mogens
authors.initials: M
authors.lastname: Johannsen
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Bøtker
authors.forename: Torsten Toftegaard
authors.initials: TT
authors.lastname: Nielsen
mesh_terms: D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008293:Malates / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D008293:Malates; D017382:Reactive Oxygen Species; D000625:Aminooxyacetic Acid; D001224:Aspartic Acid; C030298:malic acid; D005947:Glucose