INVESTIGATING APOA1 AND HDL-MEDIATED PROTECTION AGAINST DOXORUBICIN-INDUCED CARDIOTOXICITY

Abstract

Doxorubicin (DOX) is one of the most commonly used chemotherapeutic agents in human cancer therapy, but the clinical use of DOX is restricted by its dose-dependent cardiac toxicity. Therapies based on high-density lipoprotein (HDL) or its major protein, apolipoprotein (Apo) A1 can specifically protect the heart against doxorubicin (DOX)- induced apoptosis and atrophy without affecting DOX anti-tumor activity, as demonstrated in this thesis. In vitro, HDL, but not ApoA1, decreased apoptosis and atrophy in neonatal cardiomyocytes but did not provide protection to breast tumor cells against DOX cytotoxicity. Both ApoA1 and HDL were cardioprotective against DOX cardiomyocyte apoptosis and atrophy in mice bearing tumors, while still providing tumor suppression. Mechanistically, we demonstrated that ApoA1-induced cardioprotection required hepatic expression of the HDL receptor, scavenger receptor class B type I (SR-B1), but not expression of SR-B1 in cardiomyocytes. These results reveal that the liver, but not the cardiomyocyte, is a key site mediating the protective effect of ApoA1 against the cardiotoxicity of chemotherapy. These findings provide new evidence for the specific role of HDL-SR-B1 interactions in cardiomyocytes and liver and set the foundation for strategies to reduce cardiotoxicity during cancer treatment while maintaining its anti-cancer effect.