l-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation

Eur J Pharmacol. 2017 Jun 5:804:7-12. doi: 10.1016/j.ejphar.2017.04.003. Epub 2017 Apr 6.

Abstract

Radiation-induced heart damage (RIHD) is now considered to be one of the causes of mortality in cancer patients undergoing radiotherapy. Cardiac function impairments are clinical manifestations of RIHD. L-carnitine shows protective effects against irradiation and heart disease. This study was aimed to investigate the cardioprotective effects and potential molecular mechanisms of L-carnitine against RIHD. Mouse hearts were exposed to γ-radiation to induce RIHD. L-carnitine at doses of 100mg/Kg and 200mg/Kg was used to treat animals intraperitoneally. Additionally, a specific inhibitor of p38 MAPK was used to treat animals by intraperitoneal injections. Cardiac systolic/diastolic functions were determined using invasive hemodynamic methods; myocyte apoptosis was assessed using the TUNEL assay; intracellular reactive oxygen species production was measured using DHE staining; and western blotting was used to evaluate the phosphorylation of p38MAPK, phosphorylation of Nrf2, and expression levels of HO1, NQO1, caspase3 and bax. L-carnitine treatments inhibited irradiation induced cardiac function impairments. Radiation exposure induced myocyte apoptosis and reactive oxygen species production, which were attenuated by L-carnitine treatments. However, administration of a p38 MAPK inhibitor (SB203580) dramatically impaired L-carnitine's effect on attenuating apoptosis, reactive oxygen species accumulation and cardiac functions in irradiated hearts. Our study showed that L-carnitine administration activated p38MAPK/Nrf2 signalling, initiating the expression of HO1 and NQO1, which have anti-apoptotic and anti-oxidative effects, respectively. In conclusion, L-carnitine attenuates cardiac function loss by inhibiting reactive oxygen species production and apoptosis in hearts exposed to radiation. The cardioprotective effects of L-carnitine were mediated by p38MAPK/Nrf2 signalling.

Keywords: Apoptosis; Cardiac function; L-carnitine; Radiation-induced heart damage; Reactive oxygen species.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Carnitine / pharmacology*
  • Cytoprotection / drug effects
  • Dose-Response Relationship, Drug
  • Heart / drug effects
  • Heart / radiation effects*
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / radiation effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / metabolism*
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Protein Kinase Inhibitors / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Antioxidants
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • p38 Mitogen-Activated Protein Kinases
  • Carnitine