Cardiac peroxynitrite formation and left ventricular dysfunction followingdoxorubicin treatment in mice

Citation
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
ISSN journal
00223565 → ACNP
Volume
294
Issue
1
Year of publication
2000
Pages
396 - 401
Database
ISI
SICI code
0022-3565(200007)294:1<396:CPFALV>2.0.ZU;2-O
Abstract
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.