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Research ArticleCARDIOVASCULAR

Cardiac Peroxynitrite Formation and Left Ventricular Dysfunction following Doxorubicin Treatment in Mice

David M. Weinstein, Michael John Mihm and John Anthony Bauer
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 396-401;
David M. Weinstein
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Michael John Mihm
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John Anthony Bauer
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Abstract

Selective cardiotoxicity of doxorubicin remains a significant and dose-limiting clinical problem. The mechanisms involved have not been fully defined but may involve the production of reactive oxygen species and/or alteration of cardiac energetics. Here, we tested the hypotheses that doxorubicin causes left ventricular dysfunction in mice and is associated with dysregulation of nitric oxide in cardiac tissue, leading to the accumulation of 3-nitrotyrosine (a biomarker of peroxynitrite formation). Animals were dosed with doxorubicin (20 mg/kg i.p.), and left ventricular performance was assessed in vivo using M-mode and Doppler echocardiography. Five days after doxorubicin administration, left ventricular fractional shortening, cardiac output, and stroke volume parameters were significantly reduced relative to control values (30.0 ± 3.6 versus 46.1 ± 1.6%, 8.9 ± 0.9 versus 11.5 ± 0.6 ml/min, and 21.2 ± 0.1 versus 29.5 ± 0.1 μl for doxorubicin versus control,P < .05). Statistically significant (P < .05) increases in the immunoprevalence of myocardial inducible nitric oxide synthase (33 ± 18 versus 9 ± 2%, via quantitative image analysis) and 3-nitrotyrosine formation (56 ± 24 versus 0.3 ± 0.4%) were also observed after doxorubicin. Correlation analyses revealed a highly significant inverse relationship between left ventricular fractional shortening and cardiac 3-nitrotyrosine immunoprevalence (P < .01). No such relationship was observed for inducible nitric oxide synthase. Western blot analyses of cardiac myofibrillar fractions revealed extensive nitration of an abundant 40-kDa protein, shown to be the myofibrillar isoform of creatine kinase. These data demonstrate that alteration of cardiac nitric oxide control and attendant peroxynitrite formation may be an important contributor to doxorubicin-induced cardiac dysfunction. Furthermore, nitration of key myofibrillar proteins and alteration of myocyte energetics are implicated.

Footnotes

  • Send reprint requests to: Dr. John Anthony Bauer, 412 Riffe Bldg., 500 West 12th Ave., Columbus, OH 43210-1291. E-mail:bauer.140{at}osu.edu

  • ↵1 This work was supported in part by National Institutes of Health Grant HL59791 and the American Heart Association, Ohio-West Virginia Affiliates.

  • Abbreviations:
    DOX
    doxorubicin
    LV
    left ventricular
    NO
    nitric oxide
    NOS
    NO synthase
    O⨪2
    superoxide anion
    ONOO−
    peroxynitrite
    3-NT
    3-nitro-l-tyrosine, M-CK, myofibrillar creatine kinase
    • Received December 2, 1999.
    • Accepted March 10, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleCARDIOVASCULAR

Cardiac Peroxynitrite Formation and Left Ventricular Dysfunction following Doxorubicin Treatment in Mice

David M. Weinstein, Michael John Mihm and John Anthony Bauer
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 396-401;

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Research ArticleCARDIOVASCULAR

Cardiac Peroxynitrite Formation and Left Ventricular Dysfunction following Doxorubicin Treatment in Mice

David M. Weinstein, Michael John Mihm and John Anthony Bauer
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 396-401;
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