Please use this identifier to cite or link to this item:
10.1111/bph.13004
Title: | Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction |
Authors: | 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. Faculty of Pharmacy |
Keywords: | 3.1 Basic medicine;1.1. Scientific article indexed in Web of Science and/or Scopus database;Pharmacology |
Issue Date: | Mar-2015 |
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 |
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. |
Description: | Publisher Copyright: © 2014 The British Pharmacological Society. |
DOI: | 10.1111/bph.13004 |
ISSN: | 0007-1188 |
Appears in Collections: | Research outputs from Pure / Zinātniskās darbības rezultāti no ZDIS Pure |
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File | Size | Format | |
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Inhibition_of_L_carnitine.pdf | 1.77 MB | Adobe PDF | View/Open |
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