Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction
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Date
2015-03
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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.
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Publisher Copyright: © 2014 The British Pharmacological Society.
Keywords
3.1 Basic medicine, 1.1. Scientific article indexed in Web of Science and/or Scopus database, Pharmacology
Citation
Liepinsh, E, Makrecka-Kuka, M, Kuka, J, Vilskersts, R, Makarova, E, Cirule, H, Loza, E, Lola, D, Grinberga, S, Pugovics, O, Kalvins, I & Dambrova, M 2015, 'Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction', British Journal of Pharmacology, vol. 172, no. 5, pp. 1319-1332. https://doi.org/10.1111/bph.13004