title: Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury.
abstract: OBJECTIVE
  Infarct-remodelled hearts are less amenable to protection against ischaemia/reperfusion. Understanding preservation of energy metabolism in diseased vs. healthy hearts may help to develop anti-ischaemic strategies effective also in jeopardized myocardium.
  
  
  RESULTS
  Isolated infarct-remodelled/sham Sprague-Dawley rat hearts were perfused in the working mode and subjected to 15 min of ischaemia and 30 min of reperfusion. Protection of post-ischaemic ventricular work was achieved by pharmacological conditioning with sevoflurane. Oxidative metabolism was measured by substrate flux in fatty acid and glucose oxidation using [(3)H]palmitate and [(14)C]glucose. Mitochondrial oxygen consumption was measured in saponin-permeabilized left ventricular muscle fibres. Activity assays of citric acid synthase, hydroxyacyl-CoA dehydrogenase, and pyruvate dehydrogenase and mass spectrometry for acylcarnitine profiling were also performed. Six weeks after coronary artery ligation, the hearts exhibited macroscopic and molecular signs of hypertrophy consistent with remodelling and limited respiratory chain and citric acid cycle capacity. Unprotected remodelled hearts showed a marked decline in palmitate oxidation and acetyl-CoA energy production after ischaemia/reperfusion, which normalized in sevoflurane-protected remodelled hearts. Protected remodelled hearts also showed higher β-oxidation flux as determined by increased oxygen consumption with palmitoylcarnitine/malate in isolated fibres and a lower ratio of C16:1+C16OH/C14 carnitine species, indicative of a higher long-chain hydroxyacyl-CoA dehydrogenase activity. Remodelled hearts exhibited higher PPARα-PGC-1α but defective HIF-1α signalling, and conditioning enabled them to mobilize fatty acids from endogenous triglyceride stores, which closely correlated with improved recovery.
  
  
  CONCLUSIONS
  Protected infarct-remodelled hearts secure post-ischaemic energy production by activation of β-oxidation and mobilization of fatty acids from endogenous triglyceride stores.
authors.affiliation: Cardiovascular Research Centre,  University of Alberta, Edmonton,  Canada.
authors.forename: Phing-How
authors.initials: PH
authors.lastname: Lou
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.forename: Markus
authors.initials: M
authors.lastname: Heck
authors.forename: Andreas
authors.initials: A
authors.lastname: Affolter
authors.forename: Manoj
authors.initials: M
authors.lastname: Gandhi
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D019194:Ischemic Preconditioning; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000032:analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077149:Sevoflurane; D014157:Transcription Factors / Q000032:analysis; D014280:Triglycerides / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D005227:Fatty Acids; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008738:Methyl Ethers; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D014280:Triglycerides; D000077149:Sevoflurane