Department of Physiology, Development and Neuroscience, University of Cambridge, London, United Kingdom; Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, London, United Kingdom
Sophie Dieckmann
Department of Physiology, Development and Neuroscience, University of Cambridge, London, United Kingdom
Dominika Krzyzanska
Department of Physiology, Development and Neuroscience, University of Cambridge, London, United Kingdom
Dominic Manetta-Jones
Department of Physiology, Development and Neuroscience, University of Cambridge, London, United Kingdom
James A West
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, London, United Kingdom
Cecilia Castro
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, London, United Kingdom
Julian L Griffin
Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, London, United Kingdom; Section of Biomolecular Medicine, Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
Andrew J Murray
Department of Physiology, Development and Neuroscience, University of Cambridge, London, United Kingdom
Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.
