Life-threatening cardiomyopathy and heart failure are common side effects of a number of chemotherapy drugs, such as the anthracycline family of antibiotics (e.g. doxorubicin, daunorubicin) and the tyrosine kinase inhibitors (e.g. imatinib, sunitinib). Doxorubicin (DOX) is one of the most frequently used chemotherapeutic agents and the most well-known cause of chemotherapy-induced cardiac toxicity. Therefore I choose to evaluate chemoresistance against DOX in this proposal using mice and primary cardiomyocytes. DOX cardiotoxicity has been attributed to oxidative and genotoxic stress-induced apoptotic cell death of cardiomyocytes. Therefore, protection of myocardial tissue from apoptosis is central to prevent DOX-induced cardiomyopathy. Although DOX cardiotoxicity has been extensively studied, successful therapeutic strategies are still unavailable. Previous work from the laboratory of my mentor, Dr. Joan Taylor, has identified focal adhesion kinase (FAK) as a critical protective molecule against myocyte apoptosis in the heart. Most recently, I demonstrated that FAK-dependent protection against DOX cardiotoxicity was mediated by the cyclin- dependent kinase (CDK) inhibitor (CDKI) p21Cip1/WAF1 (p21). Previous studies regarding CDKIs including p21 in cardiomyocytes have been largely focused on proliferation and hypertrophy. Here, my results support a novel function of p21 in regulation of chemoresistance and apoptosis in the heart. As an extension of this work, my long-term goal is to establish participation of CDKIs in cardiomyocyte survival signaling. Working towards this goal, the objective in my K99/R00 application is to determine the regulation of p21 in cardiomyocytes and further explore p21-mediated protection against DOX cardiotoxicity. The central hypothesis is that myocardial p21 levels determine resistance to DOX-induced myocyte apoptosis and cardiomyopathy. I plan to test the central hypothesis by accomplishing the following three specific aims: 1) Investigate the expression and degradation of p21 in cardiomyocytes [mentored];2) Define mechanisms of p21-mediated resistance to DOX cardiotoxicity [independent];and 3) Demonstrate protection by p21 against DOX-induced cardiomyopathy [independent].
Data obtained from experiments proposed in this proposal will uncover a previously unrecognized function of p21Cip1/WAF1 in myocardial chemoresistance. The positive impact resulting from this work could lead to new preventive and therapeutic strategies for chemotherapy-induced cardiomyopathy.