Submitted on September 17, 2008
Revised on August 31, 2009
Accepted on September 11, 2009
Neuregulin-1 Attenuated Doxorubicin-Induced Decrease in Cardiac Troponins
Yun Bian, Maoyun Sun, Marcy Silver, kalon KL Ho, Mark A Marchionni, Anthony O Caggiano, James R. Stone1, Ivo Amende2, Thomas G. Hampton, James P. Morgan3, and Xinhua Yan2*
1 Massachusetts General Hospital and Harvard Medical School
2 Caritas St. Elizabeth's Medical Center
3 Caritas St. Elizabeth's and Tufts Univ School Med
* To whom correspondence should be addressed. E-mail: xinhua.yan{at}caritaschristi.org.
Background: Neuregulin-1 (NRG1) is a potential therapeutic agent for the treatment of doxorubicin-induced heart failure. NRG1, however, activates the erbB2 receptor, which is frequently overexpressed in breast cancers. It is therefore important to understand how NRG1, via erbB2, protects the heart against doxorubicin (Dox) cardiotoxicity. Here, we studied NRG1-erbB2 signaling in Dox-treated mice hearts and in isolated neonatal rat ventricular myocytes (NRVM). Methods: Male C57BL/6 mice were treated with recombinant NRG1 before and daily after a single dose of Dox. Cardiac function was determined by catheterization. Two-week survival was analyzed by the Kaplan-Meier method. Cardiac troponins (cTnI and cTnT), and phosphorylated Akt protein levels were determined in mice hearts and in NRVM by Western blot analysis. Activation of caspases and ubiquitinylation of troponins were determined in NRVM by caspase assay and immunoprecipitation. Results: NRG1 significantly improved survival and cardiac function in Dox-treated mice. NRG1 reduced the decrease in cTnI, cTnT and cTnC and maintained Akt phosphorylation in Dox-treated mice hearts. NRG1 reduced the decrease in cTnI and cTnT mRNA and proteins in Dox-treated NRVM. Inhibition of erbB2, PI3K, Akt and mTOR blocked the protective effects of NRG1 on cTnI and cTnT in NRVM. NRG1 significantly reduced Dox-induced caspase activation, which degraded troponins, in NRVM. NRG1 reduced Dox-induced proteasome degradation of cTnI. Conclusion: NRG1 attenuates Dox-induced decrease in cardiac troponins by increasing transcription and translation, by inhibiting caspase activation, and inhibiting proteasome degradation of troponin proteins. NRG1 maintains cardiac troponins by the erbB2-PI3K pathway which may lessen Dox-induced cardiac dysfunction. Key words: erbB2, troponin proteins, signaling, doxorubicin
