Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production

Frontiers in Physiology
Gennaro RiccioNicola Maurea

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 ...Continue Reading

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May 1, 2018·Journal of Cardiovascular Medicine·Christian Cadeddu DessalviGiuseppe Mercuro
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Mar 11, 2020·Antioxidants & Redox Signaling·Christian Cadeddu DessalviGiuseppe Mercuro
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Jan 7, 2021·Heart Failure Reviews·Diana GonciarLucia Agoston-Coldea
Nov 24, 2019·European Journal of Pharmacology·Nanthip PrathumsapNipon Chattipakorn

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Methods Mentioned

BETA
PCR

Software Mentioned

OriginPro
SPSS
ImageJ

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