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

Inotek Pharmaceuticals Corp, Beverly, Mass 01915, USA.
Circulation (Impact Factor: 14.43). 03/2003; 107(6):896-904. DOI: 10.1161/01.CIR.0000048192.52098.DD
Source: PubMed


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.
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.
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.


Available from: Michael S Wolin
    • "However, the mechanisms by which doxorubicin induces cardiac injury and dysfunction are incompletely understood. A number of doxorubicin biochemical changes have been identified that can damage cardiac reactive oxygen species (ROS),[4] production of reactive nitrogen species,[5] selective inhibition of cardiac muscle gene expression,[6] disturbance of myocardial adrenergic signaling[7] and induction of cardiac cell apoptosis.[8] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The objective of this study was to evaluate the cardioprotective effect of herbal bioactive compound ammonium glycyrrhizinate against doxorubicin-induced cardiomyopathy, in experimental animals. Materials and Methods: Ammonium glycyrrhizinate (50, 100, 200 mg/kg, p.o.) was administered for four weeks in albino rats. Cardiomyopathy was induced with a dose of 2.5 mg/kg i.p. of doxorubicin on 1th, 7th, 14th, 21th, 28th day in the experimental animals. At the end of the experiment, on 29th day, serum and heart tissues were collected and hemodynamic, biochemical and histopathological studies were carried out. Results: Administration of doxorubicin in normal rats showed significant (P < 0.001) changes in body weight, feed intake, urine output, hemodynamic parameters like (blood pressure, heart rate, cardiac output) and in lipid profile (cholesterol, triglyceride, high density lipoprotein, low density lipoprotein, very low density lipoprotein) indicating cardiomyopathy symptoms. Animals treated with ammonium glycyrrhizinate significantly (P < 0.05) decreased triglyceride, cholesterol, low density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels. Moreover, high density lipoprotein (HDL) levels increased in rats treated with ammonium glycyrrhizinate as compared with the normal group. Conclusion: Ammonium glycyrrhizinate is effective in controlling serum lipid profile and cardiac complications in experimentally induced cardiomyopathy in animals.
    Indian Journal of Pharmacology 09/2014; 46(5):527-30. DOI:10.4103/0253-7613.140585 · 0.69 Impact Factor
  • Source
    • "Aldieri et al. showed that the increase in the NO amount following treatment of the cardiac cells with DOX was associated with the increase in the iNOS gene expression [12]. Pacher et al. demonstrated that following DOX administration in mice with iNOS gene deletion, cardiac functions were better conserved [24]. The trial by Weinstein et al. demonstrated immunohistochemically that the myocardial iNOS was increased upon DOX administration [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors. Materials and Methods: Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262±18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation. Results: Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3±3.4 µmol/L) was higher than those of all other groups. Conclusion: Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors.
    Turkish Journal of Haematology 03/2014; 31(1):68-74. DOI:10.4274/Tjh.2013.0013 · 0.36 Impact Factor
  • Source
    • "The increase in mitochondrial injury resulting from the lack of iNOS can be alleviated by overexpression of MnSOD [3], [4], [6]. In contrast, Pacher et al. demonstrated that ADR-induced slight improvements in the cardiac function of iNOS (−/−) mice [26]. Variations in measurements of cardiac function exist between ex vivo and in vivo methods and both methods have known limitations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adriamycin (ADR) treatment causes an imbalance in the levels of nitric oxide ((•)NO) and superoxide (O2 (•-)) production leading to cardiac injury. Previously we demonstrated that mice lacking inducible nitric oxide synthase (iNOS) have increased oxidative stress and mitochondrial injury. The molecular events leading to increased mitochondrial injury in iNOS deficient mice is unknown. ADR in the absence of iNOS preferentially activates a proapoptotic pathway without a concurrent increase in prosurvival pathways. Treatment with ADR leads to an increase in DNA binding activity of nuclear factor kappa B (NFκB) and p53 in wildtype mice. Following ADR treatment, p53, but not NFκB DNA binding activity, as well as the level of Bax, a p53 target gene, was increased in iNOS (-/-) mice. This apoptotic signaling effect in iNOS (-/-) is alleviated by overexpression of manganese superoxide dismutase (MnSOD). Increases in NFκB and p53 in ADR-treated wildtype mice did not lead to increases in target genes such as MnSOD, bcl-xL, or Bax. Moreover, co-immunoprecipitation analysis revealed that p65, a prominent member of the NFκB family, interacts with p53 in the nucleus. These results suggest that NFκB and p53 may counter act one another's actions in ADR-treated wildtype (WT) mice. Further, these results identify a novel mechanism by which oxidative stress may regulate transcription of proapoptotic genes.
    PLoS ONE 02/2014; 9(2):e89251. DOI:10.1371/journal.pone.0089251 · 3.23 Impact Factor
Show more

Similar Publications