title: Activated peroxisomal fatty acid metabolism improves cardiac recovery in ischemia-reperfusion.
abstract: Depressed oxidation of long chain fatty acids (LCFA) in heart ischemia leads to acute accumulation of LCFA metabolites that impair the functioning of the mitochondria. We hypothesized that reduced activity of carnitine palmitoyltransferase-I (CPT-I) might activate peroxisomal LCFA oxidation and protect mitochondrial function in ischemia and reperfusion. In the present study, despite the long-term threefold reduction in L-carnitine content by 3-(2,2,2-trimethylhydrazinium)-propionate, the uptake and oxidation rates of LCFA in the heart in normoxia were not significantly influenced. The significant increase in PPARα and PGC1α nuclear content, observed in this study, were followed by increased expression of genes involved in peroxisomal fatty acid oxidation (FAO) which compensated for the limited CPT-I-dependent FA transport into the mitochondria. In ischemia followed by reperfusion, the redirection of LCFA oxidation from mitochondria to peroxisomes protected the mitochondria from the accumulation of LCFA. In turn, the recovery of FAO resulted in significant reduction of myocardial infarct size. In conclusion, the decreased L-carnitine content in the heart preserves its peroxisomal and mitochondrial function after ischemia and improves cardiac recovery during reperfusion. The functional interplay between the decrease in L-carnitine and the PPARα/PGC1α pathway-induced redirection of FA metabolism protects the mitochondria against LCFA overload and provides a foundation for novel cardioprotective mechanisms.
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga, 1006, Latvia. ledgars@biomed.lu.lv
authors.forename: Edgars
authors.initials: E
authors.lastname: Liepinsh
authors.forename: Elina
authors.initials: E
authors.lastname: Skapare
authors.forename: Janis
authors.initials: J
authors.lastname: Kuka
authors.forename: Marina
authors.initials: M
authors.lastname: Makrecka
authors.forename: Helena
authors.initials: H
authors.lastname: Cirule
authors.forename: Edijs
authors.initials: E
authors.lastname: Vavers
authors.forename: Eduards
authors.initials: E
authors.lastname: Sevostjanovs
authors.forename: Solveiga
authors.initials: S
authors.lastname: Grinberga
authors.forename: Osvalds
authors.initials: O
authors.lastname: Pugovics
authors.forename: Maija
authors.initials: M
authors.lastname: Dambrova
mesh_terms: D000818:Animals; D002331:Carnitine / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009203:Myocardial Infarction / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020675:Peroxisomes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D008763:Methylhydrazines; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine