title: Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction.
abstract: OBJECTIVE
  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.
  
  
  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
  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.
authors.affiliation: Latvian Institute of Organic Synthesis, Riga, Latvia.
authors.forename: E
authors.initials: E
authors.lastname: Liepinsh
authors.forename: M
authors.initials: M
authors.lastname: Makrecka-Kuka
authors.forename: J
authors.initials: J
authors.lastname: Kuka
authors.forename: R
authors.initials: R
authors.lastname: Vilskersts
authors.forename: E
authors.initials: E
authors.lastname: Makarova
authors.forename: H
authors.initials: H
authors.lastname: Cirule
authors.forename: E
authors.initials: E
authors.lastname: Loza
authors.forename: D
authors.initials: D
authors.lastname: Lola
authors.forename: S
authors.initials: S
authors.lastname: Grinberga
authors.forename: O
authors.initials: O
authors.lastname: Pugovics
authors.forename: I
authors.initials: I
authors.lastname: Kalvins
authors.forename: M
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002331:Carnitine / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D010084:Oxidation-Reduction; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050563:gamma-Butyrobetaine Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D000644:Quaternary Ammonium Compounds; C100590:Slc22a2 protein, rat; C000602882:methyl-gamma-butyrobetaine; D005680:gamma-Aminobutyric Acid; D050563:gamma-Butyrobetaine Dioxygenase; D002331:Carnitine