Selective inhibition of OCTN2 is more effective than inhibition of gamma-butyrobetaine dioxygenase to decrease the availability of l-carnitine and to reduce myocardial infarct size

Edgars Liepinsh, Marina Makrecka, Janis Kuka, Helena Cirule, Elina Makarova, Eduards Sevostjanovs, Solveiga Grinberga, Reinis Vilskersts, Daina Lola, Einars Loza, Ilmars Stonans, Osvalds Pugovics, Maija Dambrova

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

l-Carnitine is a cofactor in the energy metabolism pathways where it drives the uptake and oxidation of long chain fatty acids (LCFA) by mitochondria. LCFA lipotoxicity causes mitochondrial damage and results in an insufficient energy supply and a decrease in l-carnitine content limits LCFA flux and protects mitochondria. Here, we tested whether the inhibition of GBB dioxygenase (BBOX) or organic cation transporter 2 (OCTN2) is the most effective strategy to decrease l-carnitine content. The activity of 51 compounds was tested and we identified selective inhibitors of OCTN2. In contrast to selective inhibitors of BBOX, OCTN2 inhibitors induced a 10-fold decrease in l-carnitine content in the heart tissues and a significant 35% reduction of myocardial infarct size. In addition, OCTN2 inhibition correlated with the inhibitor content in the heart tissues, and OCTN2 could potentially be an efficient target to increase drug transport into tissues and to reduce drug elimination by urine. In conclusion, the results of this study confirm that selective inhibition of OCTN2, compared to selective inhibition of BBOX, is a far more effective approach to decrease l-carnitine content and to induce cardioprotective effects. OCTN2 could potentially be an efficient tool to increase drug transport in tissues and to reduce drug elimination via urine.

Original languageEnglish
Pages (from-to)33-38
Number of pages6
JournalPharmacological Research
Volume85
DOIs
Publication statusPublished - Jul 2014

Keywords

  • Biosynthesis
  • Cardioprotection
  • Drug delivery
  • Reabsorbtion in kidneys
  • Transport

Field of Science

  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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