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Journal Articles Cardiovascular Research Year : 2021

Mechanism of succinate efflux upon reperfusion of the ischaemic heart

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Hiran Prag
Anja Gruszczyk
Margaret Huang
Timothy Beach
  • Function : Author
Timothy Young
Laura Tronci
  • Function : Author
Efterpi Nikitopoulou
  • Function : Author
John Mulvey
Raimondo Ascione
Anna Hadjihambi
Michael Shattock
Kourosh Saeb-Parsy
Christian Frezza
Andrew James
  • Function : Author
Thomas Krieg
Michael Murphy
Dunja Aksentijević

Abstract

Abstract Aims Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. Methods and results To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. Conclusion Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.
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Dates and versions

hal-03366637 , version 1 (05-10-2021)

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Attribution - CC BY 4.0

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Hiran Prag, Anja Gruszczyk, Margaret Huang, Timothy Beach, Timothy Young, et al.. Mechanism of succinate efflux upon reperfusion of the ischaemic heart. Cardiovascular Research, 2021, 117 (4), pp.1188-1201. ⟨10.1093/cvr/cvaa148⟩. ⟨hal-03366637⟩

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