Abstract 21144: Doxorubicin-induced Cardiac and Hepatic Toxicity is Mediated by Protease-activated Receptor 1 (PAR-1)
Objectives: The administration of the anti-cancer drug anthracycline doxorubicin (Dox) is limited by its cardiac and hepatic cytotoxicity. Low molecular weight heparin administration has been shown to diminish the deleterious toxic Dox effects in a rat model. The objective of this study was to determine the role of PAR-1 in the cytotoxic effects of Dox.
Methods: PAR-1−/− and wild-type (WT) mice littermates were injected with Dox (20mg/kg, i.p.). Heart and liver function parameters were analyzed 5 days after Dox administration.
Results: Left ventricular function was preserved in Dox-treated PAR-1−/− mice compared to Dox-treated WT littermates (fractional shortening: 53.7±1.8% vs. 43.9±2.0% P<0.05). Par-1−/− mice expressed reduced levels of 3-nitrotyrosin, TNFα and MPO compared to WT mice. Furthermore, Dox-treated PAR-1−/− mice hearts exhibited higher levels of phosphorylated AKT, which is a protective, and less acetylation of pro-apoptotic p53 compared to treated WT littermates. In addition, liver damage (involvement), measured by circulating alkaline phosphatase levels, was less severe in PAR-1−/− compared to WT mice after Dox administration. Also, livers of treated PAR-1−/− exhibited less TNFα expression compared to treated WT mice.
Conclusions: The results indicate that PAR-1 mediates Dox-induced cardiac and hepatic injury by enhancing inflammation and apoptosis. Administration of selective PAR-1 antagonist might be beneficial in treatment of Dox-induced cardiac and hepatic toxicity.
- © 2010 by American Heart Association, Inc.