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Media type:
E-Article
Title:
β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery
Contributor:
Lindsay, Ross T;
Dieckmann, Sophie;
Krzyzanska, Dominika;
Manetta-Jones, Dominic;
West, James A;
Castro, Cecilia;
Griffin, Julian L;
Murray, Andrew J
imprint:
eLife Sciences Publications, Ltd, 2021
Published in:eLife
Language:
English
DOI:
10.7554/elife.71270
ISSN:
2050-084X
Origination:
Footnote:
Description:
<jats:p>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.</jats:p>