Repository logo
 

β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Dieckmann, Sophie 
Krzyzanska, Dominika 
Manetta-Jones, Dominic 
West, James A 

Abstract

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.

Description

Keywords

Biochemistry, Heart, Cell biology, Rat, Cardiomyocyte, Ischaemia, Langendorff, Chemical Biology

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X

Volume Title

10

Publisher

Sponsorship
British Heart Foundation (FS/14/59/31282)
Research Councils UK (EP/E500552/1)