Perturbation of microRNAs in rat heart during chronic doxorubicin treatment

PLoS One. 2012;7(7):e40395. doi: 10.1371/journal.pone.0040395. Epub 2012 Jul 31.

Abstract

Anti-cancer therapy based on anthracyclines (DNA intercalating Topoisomerase II inhibitors) is limited by adverse effects of these compounds on the cardiovascular system, ultimately causing heart failure. Despite extensive investigations into the effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown. MicroRNAs are endogenously transcribed non-coding 22 nucleotide long RNAs that regulate gene expression by decreasing mRNA stability and translation and play key roles in cardiac physiology and pathologies. Increasing doses of doxorubicin, but not etoposide (a Topoisomerase II inhibitor devoid of cardiovascular toxicity), specifically induced the up-regulation of miR-208b, miR-216b, miR-215, miR-34c and miR-367 in rat hearts. Furthermore, the lowest dosing regime (1 mg/kg/week for 2 weeks) led to a detectable increase of miR-216b in the absence of histopathological findings or alteration of classical cardiac stress biomarkers. In silico microRNA target predictions suggested that a number of doxorubicin-responsive microRNAs may regulate mRNAs involved in cardiac tissue remodeling. In particular miR-34c was able to mediate the DOX-induced changes of Sipa1 mRNA (a mitogen-induced Rap/Ran GTPase activating protein) at the post-transcriptional level and in a seed sequence dependent manner. Our results show that integrated heart tissue microRNA and mRNA profiling can provide valuable early genomic biomarkers of drug-induced cardiac injury as well as novel mechanistic insight into the underlying molecular pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antibiotics, Antineoplastic / toxicity*
  • Biomarkers / metabolism
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / metabolism
  • Doxorubicin / pharmacology
  • Doxorubicin / toxicity*
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Muscle Proteins / metabolism
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transcriptional Activation / drug effects
  • Transcriptome
  • Up-Regulation / drug effects
  • Vacuoles / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibiotics, Antineoplastic
  • Biomarkers
  • GTPase-Activating Proteins
  • MicroRNAs
  • Muscle Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Doxorubicin

Grants and funding

This study was supported by the HESI Application of Genomics to Mechanism-Based Risk Assessment Technical Committee, whose work is funded through the International Life Sciences Institute (ILSI) and the Health and Environmental Sciences Institutes (HESI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.