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Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction
Author(s) -
Liepinsh E,
MakreckaKuka M,
Kuka J,
Vilskersts R,
Makarova E,
Cirule H,
Loza E,
Lola D,
Grinberga S,
Pugovics O,
Kalvins I,
Dambrova M
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13004
Subject(s) - carnitine , chemistry , beta oxidation , in vivo , fatty acid , peroxisome , metabolism , fatty acid metabolism , medicine , ischemia , biochemistry , endocrinology , pharmacology , biology , receptor , microbiology and biotechnology
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 ( M ethyl‐ GBB ), which inhibits γ‐butyrobetaine dioxygenase ( IC 50 3 μM) and organic cation transporter 2 ( OCTN 2, IC 50 3 μM), and, in turn, decreases levels of L ‐carnitine and acylcarnitines in heart tissue. M ethyl‐ GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with M ethyl‐ GBB , uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. M ethyl‐ GBB (5 or 20 mg·kg −1 ) decreased the infarct size by 45–48%. In vivo pretreatment with M ethyl‐ 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 OCTN 2 represents an effective strategy to protect the heart against ischaemia–reperfusion‐induced damage. M ethyl‐ GBB treatment exerted cardioprotective effects and increased survival by limiting long‐chain fatty acid oxidation and facilitating glucose metabolism.