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.
Highlights
Hepatic ketogenesis plays a vital role in starvation physiology, whereby acetyl-coenzyme A derived from fatty acid oxidation (FAO) undergoes a stepwise conversion to acetoacetate (AcAc) and b-hydroxybutyrate (b-OHB), which in turn act as fuels for the brain and other extrahepatic tissues (Puchalska and Crawford, 2017)
Whilst most myocardial b-OHB appeared to result from reverse flux through succinyl-CoA:3-oxaloacid CoA transferase (SCOT), we unexpectedly found that at least some bOHB production occurred via the production of HMG-CoA by HMGCS2
A recent preliminary report suggested that heart-specific overexpression of HMGCS2 resulted in increased cardiac b-OHB, along with mitochondrial swelling and systolic impairment (Zenimaru et al, 2018). In line with this latter report, we found that inhibition of HMGCS2 was associated with protection of mitochondrial respiratory capacity in the post-ischaemic rat heart and enhanced functional recovery from ischaemia/reperfusion
Summary
Hepatic ketogenesis plays a vital role in starvation physiology, whereby acetyl-coenzyme A (acetylCoA) derived from fatty acid oxidation (FAO) undergoes a stepwise conversion to acetoacetate (AcAc) and b-hydroxybutyrate (b-OHB), which in turn act as fuels for the brain and other extrahepatic tissues (Puchalska and Crawford, 2017). The myocardial accumulation and efflux of b-OHB during ischaemia thereby mirrored that of lactate (Figure 2C–D) In this protocol, cardiac contractile function recovered to 100% of its pre-ischaemic level upon reperfusion (Figure 2—figure supplement 1). Hymeglusin administration led to a 7.6-fold ischaemic accumulation of acetoacetyl-CoA (a substrate for HMGCS2), and a 65% lower level of HMG-CoA (Figure 5D–E; both p
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