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

Autor: Cecilia Castro, Sophie Dieckmann, Ross T. Lindsay, James A. West, Andrew J. Murray, Dominic Manetta-Jones, Julian L. Griffin, Dominika Krzyzanska
Přispěvatelé: Lindsay, Ross T [0000-0001-7760-613X], Apollo - University of Cambridge Repository
Rok vydání: 2021
Předmět:
Hydroxymethylglutaryl-CoA Synthase
Male
Langendorff heart
Myocardial Ischemia
cardiomyocyte
Ketone Bodies
Ischaemia
Biochemistry
chemistry.chemical_compound
Ischemia
Tandem Mass Spectrometry
Myocytes
Cardiac
Biology (General)
3-Hydroxybutyric Acid
ATP synthase
biology
General Neuroscience
Langendorff
Heart
General Medicine
Mitochondria
HMG-CoA reductase
Ketone bodies
Medicine
Oxidation-Reduction
Research Article
medicine.medical_specialty
QH301-705.5
Science
Sodium
Citric Acid Cycle
chemistry.chemical_element
General Biochemistry
Genetics and Molecular Biology
Biochemistry and Chemical Biology
Lactate dehydrogenase
Internal medicine
Chemical Biology
medicine
Animals
Rats
Wistar
General Immunology and Microbiology
Cell Biology
medicine.disease
Rats
Endocrinology
chemistry
biology.protein
Rat
Flux (metabolism)
Chromatography
Liquid
Zdroj: eLife, Vol 10 (2021)
eLife
ISSN: 2050-084X
Popis: 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.
Databáze: OpenAIRE
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