Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction
Why the study?
Does peroxynitrite neutralization with FP15 or iNOS inhibition prevent doxorubicin-induced cardiac dysfunction and mortality in rodent models?
Population
Rodent models (mice and rats) of doxorubicin (DOX)-induced cardiac dysfunction
Comparison
FP15, aminoguanidine, or genetic deletion of… vs Control or N-nitro-L-arginine methyl ester
Design
Preclinical
Follow-up
5 days (acute model) and unspecified chronic model
Authors
Discussion
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Implication
May support peroxynitrite neutralization against doxorubicin cardiotoxicity; hypothesis-generating and leaves open human translation.
Key Points
- To determine the pathogenetic role of peroxynitrite in doxorubicin-induced cardiotoxicity and evaluate the protective efficacy of the peroxynitrite decomposition catalyst FP15.
- Administered doxorubicin (25 mg/kg IP) to wild-type and inducible nitric oxide synthase knockout mice to evaluate mortality and left ventricular performance after five days.
- Treated rodent models with the peroxynitrite decomposition catalyst FP15, the inducible nitric oxide synthase inhibitor aminoguanidine, or the endothelial nitric oxide synthase inhibitor L-NAME.
- Measured serum cardiac enzymes (LDH, creatine kinase), myocardial lipid peroxidation, nitrotyrosine formation, metalloproteinase activation, and doxorubicin antitumor efficacy.
- FP15, inducible nitric oxide synthase inhibition, and inducible nitric oxide synthase gene deletion significantly reduced doxorubicin-induced mortality and preserved left ventricular performance.
- FP15 prevented doxorubicin-induced increases in serum LDH, creatine kinase, myocardial lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation without altering superoxide generation or diminishing antitumor efficacy.
- FP15 reduced myocardial ischemic injury in rats and improved cardiac function and survival in a chronic rodent model of doxorubicin cardiotoxicity.
Structured PICO
Does peroxynitrite neutralization with FP15 or iNOS inhibition prevent doxorubicin-induced cardiac dysfunction and mortality in rodent models?
P
Population
Rodent models (mice and rats) of doxorubicin (DOX)-induced cardiac dysfunction
I
Intervention
FP15 (metalloporphyrinic peroxynitrite decomposition catalyst), aminoguanidine (inducible nitric oxide synthase inhibitor), or genetic deletion of inducible nitric oxide synthase
C
Comparator
Control (DOX alone) or N-nitro-L-arginine methyl ester (endothelial nitric oxide synthase inhibitor)
O
Outcome
Left ventricular performance and mortalitysurrogate
Peroxynitrite plays a key pathogenetic role in doxorubicin-induced heart failure, and its neutralization represents a potential cardioprotective strategy.
Cite This Study
Pacher et al. (2003) studied this question.