Abstract 2168: The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy
Background: Doxorubicin is a frequently used anticancer drug. One major factor limiting its clinical application is doxorubicin induced cardiotoxicity characterized by left ventricular (LV) dysfunction and congestive heart failure. The molecular mechanism of doxorubicin-mediated cardiomyopathy is not fully understood. However, several lines of evidence indicate that endothelin-1 (ET-1) plays an essential role in the pathogenesis of doxorubicin cardiotoxicity. First, endothelin plasma levels are increased following doxorubuicin administration. Second, cardiac specific overexpression of ET-1 in mice resulted in a cardiomyopathy similar to the one induced by doxorubicin. We therefore hypothesized that doxorubicin increases endothelin-1 expression in heart and that administration of the endothelin receptor blocker bosentan inhibits the doxorubicin induced cardiomyopathy.
Methods & Results: Regulation of ET-1 and endothelin receptors by doxorubicin in vivo was analyzed in C57BL/10 mice following treatment with doxorubicin (20 mg/kg) using quantitative rt-PCR and ELISA assays. Cardiac function was analyzed by a microconductance catheter. We observed a significant increase of cardiac ET-1 expression to about 300% (RNA) and 170% (protein) compared to saline treated controls. LV function was significantly impaired (eg left ventricular pressure, LVP: 95 ± 6 vs 67 ± 6 mm Hg for control and doxorubicin treatment, respectively; P < 0.005). Cardiac expression of ETA and ETB receptors was not affected by doxorubicin administration. Consequently, treatment of mice with bosentan (100 mg/kg) prior to doxorubicin strikingly inhibited the doxorubicin-induced cardiotoxicity with preserved indices of contractility (LVP: 88 ± 5 mm Hg following doxorubicin after pre-treatment with bosentan; P = n. s. vs. control).
Conclusion: These data indicate a key role for ET-1 in mediating cardiotoxic effects of doxorubicin. Inhibition of ET-1 effects by bosentan may be of therapeutic benefit for patients receiving doxorubicin.