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

5 Citations (Scopus)

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

Fingerprint

Reactive Oxygen Species
Oxidation-Reduction
Isoproterenol
Ranolazine
Trastuzumab
Natriuretic Peptides
Matrix Metalloproteinase 2
Workload
Caspase 3
Doxorubicin
Muscle Cells
Oxidative Stress
Fluorescence
Cardiotoxicity
Messenger RNA
Survival

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production. / Riccio, Gennaro; Antonucci, Salvatore; Coppola, Carmela; D'Avino, Chiara; Piscopo, Giovanna; Fiore, Danilo; Maurea, Carlo; Russo, Michele; Rea, Domenica; Arra, Claudio; Condorelli, Gerolama; Di Lisa, Fabio; Tocchetti, Carlo G.; De Lorenzo, Claudia; Maurea, Nicola.

In: Frontiers in Physiology, Vol. 9, No. FEB, 38, 06.02.2018.

Research output: Contribution to journalArticle

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, CG, De Lorenzo, C & Maurea, N 2018, 'Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production', Frontiers in Physiology, vol. 9, no. FEB, 38. https://doi.org/10.3389/fphys.2018.00038
Riccio, Gennaro ; Antonucci, Salvatore ; Coppola, Carmela ; D'Avino, Chiara ; Piscopo, Giovanna ; Fiore, Danilo ; Maurea, Carlo ; Russo, Michele ; Rea, Domenica ; Arra, Claudio ; Condorelli, Gerolama ; Di Lisa, Fabio ; Tocchetti, Carlo G. ; De Lorenzo, Claudia ; Maurea, Nicola. / Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production. In: Frontiers in Physiology. 2018 ; Vol. 9, No. FEB.
@article{64ee736206164c339126b69c3aa4bf21,
title = "Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production",
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.",
keywords = "Heart failure, Heart function, Oxidative stress, Ranolazine, Trastuzumab cardiotoxicity",
author = "Gennaro Riccio and Salvatore Antonucci and Carmela Coppola and Chiara D'Avino and Giovanna Piscopo and Danilo Fiore and Carlo Maurea and Michele Russo and Domenica Rea and Claudio Arra and Gerolama Condorelli and {Di Lisa}, Fabio and Tocchetti, {Carlo G.} and {De Lorenzo}, Claudia and Nicola Maurea",
year = "2018",
month = "2",
day = "6",
doi = "10.3389/fphys.2018.00038",
language = "English",
volume = "9",
journal = "Frontiers in Physiology",
issn = "1664-042X",
publisher = "Frontiers Research Foundation",
number = "FEB",

}

TY - JOUR

T1 - Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production

AU - Riccio, Gennaro

AU - Antonucci, Salvatore

AU - Coppola, Carmela

AU - D'Avino, Chiara

AU - Piscopo, Giovanna

AU - Fiore, Danilo

AU - Maurea, Carlo

AU - Russo, Michele

AU - Rea, Domenica

AU - Arra, Claudio

AU - Condorelli, Gerolama

AU - Di Lisa, Fabio

AU - Tocchetti, Carlo G.

AU - De Lorenzo, Claudia

AU - Maurea, Nicola

PY - 2018/2/6

Y1 - 2018/2/6

N2 - 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.

AB - 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.

KW - Heart failure

KW - Heart function

KW - Oxidative stress

KW - Ranolazine

KW - Trastuzumab cardiotoxicity

UR - http://www.scopus.com/inward/record.url?scp=85041827677&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041827677&partnerID=8YFLogxK

U2 - 10.3389/fphys.2018.00038

DO - 10.3389/fphys.2018.00038

M3 - Article

AN - SCOPUS:85041827677

VL - 9

JO - Frontiers in Physiology

JF - Frontiers in Physiology

SN - 1664-042X

IS - FEB

M1 - 38

ER -