Abstract P399: Endothelial Myc Deletion Reduces Doxorubicin-induced Cardiac Dysfunction And Remodeling

Abstract

Cardiotoxicity is the most common complication in patients undergoing chemotherapy, and the leading cause of death in long-term cancer survivors. Anthracyclines are highly effective drugs broadly used in cancer treatment, but with limited use due to cardiotoxicity. Currently, there is no effective treatment for anthracycline-induced cardiotoxicity. Recent studies have shown the role of endothelial cells in cardioprotection after anthracycline exposure, though mechanisms involved remain elusive. In the present study, we provide supporting evidence that endothelial Myc plays a role in anthracycline-induced cardiotoxicity. Myc is a stress sensor and master regulator involved in multiple cellular functions. Deregulated Myc expression has been linked to multiple pathological conditions. Using a conditional knockout model, we tested the hypothesis that loss of endothelial c-Myc is cardioprotective. Control (CT) and endothelial knockout (KO) juvenile mice were exposed to 15mg/kg cumulative dose of doxorubicin administered in 6 doses every 2-days along 2-weeks. Echocardiography was performed 3-days after last dose. Doxorubicin had a significant sex-specific impact in cardiac function as previously reported. In CT males, doxorubicin caused significant decline in stroke and diastolic volume, without changes in ejection fraction. In CT females, doxorubicin caused significant increase in heart rate, decline in ejection fraction, and increase in diastolic volume. KO animals showed attenuated response to these doxorubicin-induced alterations in both males and females. Pathology analysis of the heart 3-months after doxorubicin exposure showed significant decline in CT and KO male cardiac mass and collagen content, both of which were attenuated in KO animals. Doxorubicin did not show any impact on mass and collagen content in females. RNAseq analysis suggested modulation of distinct pathways in CT and KO hearts associated with inflammation, DNA damage and repair, cell death and fibrosis. Cdkn1a and TP53 were top upstream regulators predicted to be activated in CT and let-7 in KO hearts. Our findings support the potential targeting of endothelial Myc in doxorubicin-induced cardiotoxicity.