Alleviation of chemotherapy-induced cardiovascular toxicity

ABSTRACT Many cancer drugs increase cardiovascular (CV) events, including hypertension, thrombosis, and cardiomyopathy. Damaged endothelial cells (ECs) caused by chemotherapy can trigger the development and progression of cardiovascular disease (CVD). ECs represent a critical target for improving the management of chemotherapy-induced CV toxicity. The lysosomal pathway is critical to maintaining EC homeostasis. However, the role of lysosomes in chemotherapy-induced EC dysfunction and whether rescuing lysosomal function is a potential strategy to treat CV toxicity remain to be fully explored. Our preliminary data suggest that the chemotherapeutic drug doxorubicin (DOX) impairs lysosomal function in ECs. TFEB is a master regulator of autophagy and lysosome biogenesis. Our previous studies demonstrated that endothelial TFEB protects against atherosclerosis, increases glucose uptake, and improves blood flow recovery after ischemic injury, underscoring the critical role of EC TFEB in regulating CV hemostasis. Our preliminary data suggest that EC- TFEB transgene regulates DOX-induced cardiac dysfunction in mice. TFEB controls lysosomal malfunction, apoptosis, oxidative stress, and inflammation induced by DOX in human ECs. Our RNA-seq data identified multiple lysosomal-associated pathways in ECs treated with DOX. Based on the solid rationale and preliminary data, we will define the role of endothelial TFEB in CV dysfunction induced by cancer treatment. By taking advantage of our EC-specific transgenic (Tg) and knockout (KO) mouse models and the combined expertise of the assembled team, three Specific Aims are proposed. Specific Aim 1: Define the role of endothelial TFEB in cancer therapy-induced EC dysfunction and EC-cardiomyocyte interaction in vitro; Specific Aim 2: Define the role of EC TFEB in cancer therapy-induced CV toxicity in vivo; Specific Aim 3: Elucidate the mechanisms mediating the effects of EC TFEB on cancer therapy-induced cardiac dysfunction in vivo. Understanding endothelial TFEB’s role and underlying mechanisms in cancer therapy-induced CV toxicity would set a profound foundation to define endothelial TFEB as a potential therapeutic target to treat CV complications caused by cancer therapy.