Inhibition of CPT2 exacerbates cardiac dysfunction and inflammation in experimental endotoxaemia

Marina Makrecka-Kuka (Coresponding Author), Stanislava Korzh, Melita Videja, Reinis Vilskersts, Eduards Sevostjanovs, Olga Zharkova-Malkova, Pavel Arsenyan, Janis Kuka, Maija Dambrova, Edgars Liepinsh

Research output: Contribution to journalArticlepeer-review

Abstract

The suppression of energy metabolism is one of cornerstones of cardiac dysfunction in sepsis/endotoxaemia. To investigate the role of fatty acid oxidation (FAO) in the progression of inflammation-induced cardiac dysfunction, we compared the effects of FAO-targeting compounds on mitochondrial and cardiac function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia. In LPS-treated mice, endotoxaemia-induced inflammation significantly decreased cardiac FAO and increased pyruvate metabolism, while cardiac mechanical function was decreased. AMP-activated protein kinase activation by A769662 improved mitochondrial FAO without affecting cardiac function and inflammation-related gene expression during endotoxaemia. Fatty acid synthase inhibition by C75 restored both cardiac and mitochondrial FAO; however, no effects on inflammation-related gene expression and cardiac function were observed. In addition, the inhibition of carnitine palmitoyltransferase 2 (CPT2)-dependent FAO by aminocarnitine resulted in the accumulation of FAO intermediates, long-chain acylcarnitines, in the heart. As a result, cardiac pyruvate metabolism was inhibited, which further exacerbated inflammation-induced cardiac dysfunction. In conclusion, although inhibition of CPT2-dependent FAO is detrimental to cardiac function during endotoxaemia, present findings show that the restoration of cardiac FAO alone is not sufficient to recover cardiac function. Rescue of cardiac FAO should be combined with anti-inflammatory therapy to ameliorate cardiac dysfunction in endotoxaemia.

Original languageEnglish
Pages (from-to)11903-11911
Number of pages9
JournalJournal of Cellular and Molecular Medicine
Volume24
Issue number20
DOIs
Publication statusPublished - 1 Oct 2020

Keywords

  • acylcarnitine
  • endotoxaemia
  • fatty acid oxidation
  • heart
  • mitochondria

Field of Science

  • 3.1 Basic medicine
  • 1.6 Biological sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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