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Activated peroxisomal fatty acid metabolism improves cardiac recovery in ischemia-reperfusion

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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.

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Acknowledgments

This research was supported by the Taiho Foundation, ERDF grant no. 2010/0234/2DP/2.1.1.1.0/10/APIA/VIAA/063, L’Oréal Latvian fellowship “For Women in Science”, and the European Social Fund agreement no. 009/0147/1DP/1.1.2.1.2/09/IPIA/VIAA/009.

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Authors and Affiliations

  1. Latvian Institute of Organic Synthesis, Aizkraukles Str 21, Riga, 1006, Latvia

    Edgars Liepinsh, Elina Skapare, Janis Kuka, Marina Makrecka, Helena Cirule, Edijs Vavers, Eduards Sevostjanovs, Solveiga Grinberga, Osvalds Pugovics & Maija Dambrova

  2. Faculty of Pharmacy, Riga Stradins University, Dzirciema Str 16, Riga, 1007, Latvia

    Elina Skapare, Marina Makrecka, Edijs Vavers & Maija Dambrova

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  1. Edgars Liepinsh
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  2. Elina Skapare
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  3. Janis Kuka
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  4. Marina Makrecka
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  5. Helena Cirule
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  7. Eduards Sevostjanovs
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  8. Solveiga Grinberga
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  9. Osvalds Pugovics
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  10. Maija Dambrova
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Correspondence to Edgars Liepinsh.

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Liepinsh, E., Skapare, E., Kuka, J. et al. Activated peroxisomal fatty acid metabolism improves cardiac recovery in ischemia-reperfusion. Naunyn-Schmiedeberg's Arch Pharmacol 386, 541–550 (2013). https://doi.org/10.1007/s00210-013-0849-0

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  • DOI: https://doi.org/10.1007/s00210-013-0849-0

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