Dm. Weinstein et al., Cardiac peroxynitrite formation and left ventricular dysfunction followingdoxorubicin treatment in mice, J PHARM EXP, 294(1), 2000, pp. 396-401
Citations number
34
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Selective cardiotoxicity of doxorubicin remains a significant and dose-limi
ting 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 cau
ses left ventricular dysfunction in mice and is associated with dysregulati
on of nitric oxide in cardiac tissue, leading to the accumulation of 3-nitr
otyrosine (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 doxorub
icin administration, left ventricular fractional shortening, cardiac output
, and stroke volume parameters were significantly reduced relative to contr
ol 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 ml for doxorubicin versus c
ontrol, P < .05). Statistically significant (P < .05) increases in the immu
noprevalence of myocardial inducible nitric oxide synthase (33 +/- 18 versu
s 9 +/- 2%, via quantitative image analysis) and 3-nitrotyrosine formation
(56 +/- 24 versus 0.3 +/- 0.4%) were also observed after doxorubicin. Corre
lation analyses revealed a highly significant inverse relationship between
left ventricular fractional shortening and cardiac 3-nitrotyrosine immunopr
evalence (P < .01). No such relationship was observed for inducible nitric
oxide synthase. Western blot analyses of cardiac myofibrillar fractions rev
ealed extensive nitration of an abundant 40-kDa protein, shown to be the my
ofibrillar isoform of creatine kinase. These data demonstrate that alterati
on of cardiac nitric oxide control and attendant peroxynitrite formation ma
y be an important contributor to doxorubicin-induced cardiac dysfunction. F
urthermore, nitration of key myofibrillar proteins and alteration of myocyt
e energetics are implicated.