Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction

E. Liepinsh, M. Makrecka-Kuka, J. Kuka, R. Vilskersts, E. Makarova, H. Cirule, E. Loza, D. Lola, S. Grinberga, O. Pugovics, I. Kalvins, M. Dambrova

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Background and Purpose The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury. Key Results In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg-1) decreased the infarct size by 45-48%. In vivo pretreatment with Methyl-GBB (20 mg·kg-1) attenuated the infarct size by 45% and improved 24 h survival of rats by 20-30%. Conclusions and Implications Reduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia-reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism.

Original languageEnglish
Pages (from-to)1319-1332
Number of pages14
JournalBritish Journal of Pharmacology
Volume172
Issue number5
DOIs
Publication statusPublished - Mar 2015

Field of Science

  • 3.1 Basic medicine

Publication Type

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

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