title: Tolerance to ischaemic injury in remodelled mouse hearts: less ischaemic glycogenolysis and preserved metabolic efficiency.
abstract: OBJECTIVE
  Post-infarction remodelled failing hearts have reduced metabolic efficiency. Paradoxically, they have increased tolerance to further ischaemic injury. This study was designed to investigate the metabolic mechanisms that may contribute to this phenomenon and to examine the relationship between ischaemic tolerance and metabolic efficiency during post-ischaemic reperfusion.
  
  
  RESULTS
  Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or SHAM surgery. After 4 weeks, in vivo mechanical function was assessed by echocardiography, and then isolated working hearts were perfused in this sequence: 45 min aerobic, 15 min global no-flow ischaemia, and 30 min aerobic reperfusion. Left ventricular (LV) function, metabolic rates, and metabolic efficiency were measured. Relative to SHAM, both in vivo and in vitro CAL hearts had depressed cardiac function under aerobic conditions (45 and 36%, respectively), but they had a greater recovery of LV function during post-ischaemic reperfusion (67 vs. 49%, P < 0.05). While metabolic efficiency (LV work per ATP produced) was 50% lower during reperfusion of SHAM hearts, metabolic efficiency in CAL hearts did not decrease. During ischaemia, glycogenolysis was 28% lower in CAL hearts, indicative of lower ischaemic proton production. There were no differences in mitochondrial abundance, calcium handling proteins, or key metabolic enzymes.
  
  
  CONCLUSIONS
  Compared with SHAM, remodelled CAL hearts are more tolerant to ischaemic injury and undergo no further deterioration of metabolic efficiency during reperfusion. Less glycogen utilization in CAL hearts during ischaemia may contribute to increased ischaemic tolerance by limiting ischaemic proton production that may improve ion homeostasis during early reperfusion.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-43 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7 Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada Cardiovascular Research Centre, Alberta, Canada Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.
authors.forename: Waleed G T
authors.initials: WG
authors.lastname: Masoud
authors.affiliation: Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada Cardiovascular Research Centre, Alberta, Canada Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada Faculty of Pharmacy, Yarmouk University, Irbid, Jordan.
authors.forename: Osama
authors.initials: O
authors.lastname: Abo Al-Rob
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-43 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-43 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7 Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada Cardiovascular Research Centre, Alberta, Canada Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-43 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7 Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada Cardiovascular Research Centre, Alberta, Canada sandy.clanachan@ualberta.ca.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
mesh_terms: D000818:Animals; D050261:Glycogenolysis / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion / Q000379:methods; D016277:Ventricular Function, Left / Q000502:physiology
keywords: Cardiac metabolism; Glucose oxidation; Glycolysis; Ischaemic tolerance; Remodelled hearts