Overexpression of Nrdp1 in the heart exacerbates doxorubicin-induced cardiac dysfunction in mice

PLoS One. 2011;6(6):e21104. doi: 10.1371/journal.pone.0021104. Epub 2011 Jun 27.

Abstract

Background: Cardiac cell death and generation of oxidative stress contribute to doxorubicin (DOX)-induced cardiac dysfunction. E3 ligase Nrdp1 plays a critical role in the regulation of cell apoptosis, inflammation and production of reactive oxygen species (ROS), which may contribute to heart failure. However, the role of Nrdp1 in DOX-induced cardiac injury remains to be determined.

Methods and results: We examined the effect of Nrdp1 overexpression with DOX treatment in rat neonatal cardiomyocytes and mouse heart tissue. Cardiomyocytes were infected with adenovirus containing GFP (Ad-GFP), Nrdp1 wild-type (Ad-Nrdp1) or the dominant-negative form of Nrdp1 (Ad-Dn-Nrdp1), then treated with DOX for 24 hr. DOX treatment increased cell death and apoptosis, with Ad-Nrdp1 infection enhancing these actions but Ad-Dn-Nrdp1 infection attenuating these effects. Furthermore, 5 days after a single injection of DOX (20 mg/kg, intraperitoneally), Nrdp1 transgenic mice (TG) showed decreased cardiac function and increased apoptosis, autophagy and oxidative stress as compared with wild-type (WT) mice (P<0.01). Survival rate was significantly lower in Nrdp1 TG mice than in WT mice 10 days after DOX injection (P<0.01).

Conclusions/significance: These results were associated with decreased activation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Nrdp1 may be a key mediator in the development of cardiac dysfunction after DOX treatment and associated with inhibition of Akt, ERK1/2 and STAT3. Nrdp1 may be a new therapeutic target in protecting against the cardiotoxic effects of DOX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Autophagy / drug effects
  • Autophagy / genetics
  • Blotting, Western
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Doxorubicin / pharmacology*
  • Echocardiography
  • Heart / drug effects*
  • Heart / physiology*
  • Heart Ventricles / metabolism
  • In Situ Nick-End Labeling
  • Lipid Peroxidation / drug effects
  • Male
  • Malondialdehyde / metabolism
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Myocardium / metabolism*
  • Myocardium / ultrastructure
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Rats
  • Rats, Sprague-Dawley
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Ubiquitin-Protein Ligases

Substances

  • Carrier Proteins
  • STAT3 Transcription Factor
  • Malondialdehyde
  • Doxorubicin
  • Rnf41 protein, mouse
  • Ubiquitin-Protein Ligases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3