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

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Carnitine/*biosynthesis ; Fatty Acids/*metabolism ; Myocardial Infarction/*drug therapy ; Myocardial Infarction/*metabolism ; Quaternary Ammonium Compounds/*pharmacology ; gamma-Aminobutyric Acid/*analogs & derivatives; Animals ; Biological Transport/drug effects ; Dose-Response Relationship, Drug ; Male ; Molecular Structure ; Myocardial Infarction/prevention & control ; Organic Cation Transport Proteins/antagonists & inhibitors ; Organic Cation Transport Proteins/metabolism ; Organic Cation Transporter 2 ; Oxidation-Reduction ; Quaternary Ammonium Compounds/chemical synthesis ; Quaternary Ammonium Compounds/chemistry ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; gamma-Aminobutyric Acid/chemical synthesis ; gamma-Aminobutyric Acid/chemistry ; gamma-Aminobutyric Acid/pharmacology ; gamma-Butyrobetaine Dioxygenase/antagonists & inhibitors ; gamma-Butyrobetaine Dioxygenase/metabolism

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.
(© 2014 The British Pharmacological Society.)

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0 (Fatty Acids)
0 (Organic Cation Transport Proteins)
0 (Organic Cation Transporter 2)
0 (Quaternary Ammonium Compounds)
0 (Slc22a2 protein, rat)
0 (methyl-gamma-butyrobetaine)
56-12-2 (gamma-Aminobutyric Acid)
EC 1.14.11.1 (gamma-Butyrobetaine Dioxygenase)
S7UI8SM58A (Carnitine)

Date Created: 20141104 Date Completed: 20160310 Latest Revision: 20181113

20240829

PMC4337704

10.1111/bph.13004

25363063