verbatim): The discovery of doxorubicin (Dox; Adriamycin) an antitumor antibiotic 40 years ago lead to a major step in the fight against cancer. The agent was found to be effective for the treatment especially of breast cancer and leukemia and remains a major component of the therapeutic armamentarium. Unfortunately, its clinical use is limited by life threatening dose-dependent cardiac side effects that lead to degenerative cardiomyopathy and congestive heart failure. The overall aim of this proposal is to elucidate the molecular genetic mechanisms of Dox cardiotoxicity. Our studies have demonstrated that Dox selectively dysregulates the expression of cardiac-specific or cardiac-restricted genes by depleting the levels of tissue specific transcription factors and co-factors. We will investigate the central roles of MEF2C:p300 interactions and MEF2C acetylation by p300 in cardiac specific gene expression and the response to Dox. Because Dox depletes p300 protein we will study whether Dox induces selective protein degradation of p300. Since P300 and El 2 can rescue the inhibition by Dox of transcription from MEF2C and E-box dependent promoters, respectively. We will deliver both p300 and El 2 to cardiomyocytes and to rat myocardium using newly developed lentiviral vectors. Finally we will investigate the function of the Cardiac Adriamycin Responsive Protein (CARP) that inhibits cell proliferation and may be the first member of the Ink4 family of cyclin dependent kinase inhibitors described in heart. These studies will help define the mechanisms of a serious cardiac side effect of a widely used cancer therapy and potentially lead to protective approaches.
