Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production

Gennaro Riccio, Salvatore Antonucci, Carmela Coppola, Chiara D'Avino, Giovanna Piscopo, Danilo Fiore, Carlo Maurea, Michele Russo, Domenica Rea, Claudio Arra, Gerolama Condorelli, Fabio Di Lisa, Carlo G. Tocchetti, Claudia De Lorenzo, Nicola Maurea

Research output: Contribution to journalArticle

Abstract

The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab. Trastuzumab cardiotoxicity was accompanied by elevations in natriuretic peptides and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated with co-treatment with ranolazine. Trastuzumab also increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Interestingly, Neonatal Rat Ventricular Myocytes (NRVMs), labeled with MitoTracker Red and treated with trastuzumab, showed only a small increase in ROS compared to baseline conditions. We then stressed trastuzumab-treated cells with the beta-agonist isoproterenol to increase workload, and we observed a significant increase of probe fluorescence, compared with cells treated with isoproterenol alone, reflecting induction of oxidative stress. These effects were blunted by ranolazine, supporting a role for INa inhibition in the regulation of redox balance also in trastuzumab cardiotoxicity.

Original languageEnglish
Article number38
JournalFrontiers in Physiology
Volume9
Issue numberFEB
DOIs
Publication statusPublished - Feb 6 2018

Keywords

  • Heart failure
  • Heart function
  • Oxidative stress
  • Ranolazine
  • Trastuzumab cardiotoxicity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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  • Cite this

    Riccio, G., Antonucci, S., Coppola, C., D'Avino, C., Piscopo, G., Fiore, D., Maurea, C., Russo, M., Rea, D., Arra, C., Condorelli, G., Di Lisa, F., Tocchetti, C. G., De Lorenzo, C., & Maurea, N. (2018). Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production. Frontiers in Physiology, 9(FEB), [38]. https://doi.org/10.3389/fphys.2018.00038