Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Dose-Response Relationship Drug Molecular Structure Organic Cation Transport Proteins gamma-Butyrobetaine Dioxygenase Fatty Acids Myocardial Infarction Organic Cation Transporter 2 Biological Transport Research Papers Rats Quaternary Ammonium Compounds Structure-Activity Relationship Carnitine Animals Rats Wistar Oxidation-Reduction gamma-Aminobutyric Acid |
| Popis: | 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.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%.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. |
| Databáze: | OpenAIRE |
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