Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction

Pál Pacher, Lucas Liaudet, Péter Bai, Jon G. Mabley, Pawel M. Kaminski, László Virág, Amitabha Deb, Éva Szabó, Zoltán Ungvári, Michael S. Wolin, John T. Groves, Csaba Szabó

    Research output: Contribution to journalArticle

    241 Scopus citations

    Abstract

    Background - Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction. Methods and Results - Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance, In contrast, inhibition of the endothelial isoform of nitric oxide synthase with N-nitro-L-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity. Conclusions - Thus, peroxynitrite plays a key role in the pathogenesis of DOX-induced cardiac failure. Targeting peroxynitrite formation may represent a new cardioprotective strategy after DOX exposure or in other conditions associated with peroxynitrite formation, including myocardial ischemia/reperfusion injury.

    Original languageEnglish (US)
    Pages (from-to)896-904
    Number of pages9
    JournalCirculation
    Volume107
    Issue number6
    DOIs
    StatePublished - Feb 16 2003

    Keywords

    • Cardiac function
    • Doxorubicin
    • Heart failure
    • Nitric oxide
    • Oxidative stress

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine
    • Physiology (medical)

    Fingerprint Dive into the research topics of 'Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction'. Together they form a unique fingerprint.

  • Cite this

    Pacher, P., Liaudet, L., Bai, P., Mabley, J. G., Kaminski, P. M., Virág, L., Deb, A., Szabó, É., Ungvári, Z., Wolin, M. S., Groves, J. T., & Szabó, C. (2003). Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation, 107(6), 896-904. https://doi.org/10.1161/01.CIR.0000048192.52098.DD