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

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.

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  • Authors+Show Affiliations

    ,

    Inotek Pharmaceuticals Corp, Beverly, Mass 01915, USA.

    , , , , , , , , , ,

    Source

    Circulation 107:6 2003 Feb 18 pg 896-904

    MeSH

    Acute Disease
    Animals
    Catalysis
    Chronic Disease
    Creatine Kinase
    Disease Models, Animal
    Doxorubicin
    Enzyme Inhibitors
    Heart
    Heart Failure
    L-Lactate Dehydrogenase
    Male
    Metalloporphyrins
    Mice
    Mice, Inbred BALB C
    Mice, Inbred C57BL
    Mice, Knockout
    Nitric Oxide Synthase
    Nitric Oxide Synthase Type II
    Nitric Oxide Synthase Type III
    Oxidative Stress
    Peroxynitrous Acid
    Survival Rate

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    12591762

    Citation

    Pacher, Pál, et al. "Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-induced Cardiac Dysfunction." Circulation, vol. 107, no. 6, 2003, pp. 896-904.
    Pacher P, Liaudet L, Bai P, et al. Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation. 2003;107(6):896-904.
    Pacher, P., Liaudet, L., Bai, P., Mabley, J. G., Kaminski, P. M., Virág, L., ... Szabó, C. (2003). Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. Circulation, 107(6), pp. 896-904.
    Pacher P, et al. Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-induced Cardiac Dysfunction. Circulation. 2003 Feb 18;107(6):896-904. PubMed PMID: 12591762.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction. AU - Pacher,Pál, AU - Liaudet,Lucas, AU - Bai,Péter, AU - Mabley,Jon G, AU - Kaminski,Pawel M, AU - Virág,László, AU - Deb,Amitabha, AU - Szabó,Eva, AU - Ungvári,Zoltán, AU - Wolin,Michael S, AU - Groves,John T, AU - Szabó,Csaba, PY - 2003/2/20/pubmed PY - 2003/3/1/medline PY - 2003/2/20/entrez SP - 896 EP - 904 JF - Circulation JO - Circulation VL - 107 IS - 6 N2 - 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/12591762/Potent_metalloporphyrin_peroxynitrite_decomposition_catalyst_protects_against_the_development_of_doxorubicin_induced_cardiac_dysfunction_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=12591762.ui DB - PRIME DP - Unbound Medicine ER -