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

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 ?-butyrobetaine dioxygenase (IC?? 3??M) and organic cation transporter 2 (OCTN2, IC?? 3??M), 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.

SUBMITTER: Liepinsh E

PROVIDER: S-EPMC4337704 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

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

British journal of pharmacology 20150112 5

<h4>Background and purpose</h4>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.<h4 ...[more]

PMID: 25363063

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