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Vol. 294, Issue 1, 396-401, July 2000
Division of Pharmacology, College of Pharmacy, The Ohio State
University, Columbus, Ohio
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.
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