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

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Pál Pacher, Lucas Liaudet, Péter Bai, Jon G Mabley, Pawel M Kaminski, László Virág, Amitabha Deb, Eva Szabó, Zoltán Ungvári, Michael S Wolin, John T Groves, Csaba Szabó
• Journal: Circulation (Circulation) Vol. 107 Issue 6 Pg. 896-904 (Feb 18 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12591762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin
• Metalloporphyrins
• Peroxynitrous Acid
• Doxorubicin
• L-Lactate Dehydrogenase
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, mouse
• Nos3 protein, mouse
• Creatine Kinase

Topics

• Acute Disease
• Animals
• Catalysis (drug effects)
• Chronic Disease
• Creatine Kinase (blood)
• Disease Models, Animal
• Doxorubicin (toxicity)
• Enzyme Inhibitors (pharmacology)
• Heart (drug effects, physiopathology)
• Heart Failure (chemically induced, physiopathology, prevention & control)
• L-Lactate Dehydrogenase (blood)
• Male
• Metalloporphyrins (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase (antagonists & inhibitors, genetics, metabolism)
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Oxidative Stress (drug effects, genetics)
• Peroxynitrous Acid (metabolism)
• Survival Rate