Abstract 347: Endothelial Transcription Factor EB Protects Against Doxorubicin-induced Endothelial Toxicity And Cardiac Dysfunction

Objective: Doxorubicin (DOX), an effective chemotherapeutic drug for various cancers, has been demonstrated to induce cardiovascular toxicity in cancer survivors. EC dysfunction is recognized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. Transcription factor EB (TFEB), a master autophagy regulator, regulates cardiovascular homeostasis. Thus, experiments were aimed to test whether endothelial TFEB protects against EC damage and alleviates cardiac dysfunction after DOX treatment. Methods: EC-specific TFEB transgenic (EC-TFEB Tg) mice, EC-specific knockout (EC-TFEB KO) mice, and littermate controls were administered DOX by intravenous injection. Survival curves were generated, and cardiac functions were measured in mice in vivo . The effects of TFEB on mitochondrial reactive oxygen species production, autophagic flux, and apoptosis were evaluated in human and mouse cardiac microvascular ECs (CMECs) treated with DOX in vitro . Mechanistically, RNA-sequencing analysis and ChIP-qPCR were performed in DOX-treated ECs. Results: EC-TFEB Tg mice showed significantly reduced mortality and improved cardiac function, together with attenuation of perivascular fibrosis after DOX treatment. By contrast, EC-TFEB KO consistently exacerbated DOX-induced cardiac dysfunction in mice. Furthermore, we observed that TFEB enhanced autophagy and reduced oxidative stress in CMECs in response to DOX treatment. In addition, TFEB prevented EC barrier damage and alleviated proinflammatory cytokine release from CMECs, contributing to the protective effects of EC TFEB on cardiomyocytes. Mechanistically, DAB adaptor protein 2 (DAB2), a clathrin and cargo-binding endocytic adaptor protein, was identified as a TFEB target gene in ECs. Accordingly, DAB2 knockdown attenuated the inhibitory effects of TFEB on the secretion of proinflammatory cytokines from CMECs. Conclusion: Endothelial TFEB protects against DOX-induced EC damage and restricts the release of proinflammatory cytokines, thereby inhibiting cardiac dysfunction. A better understanding of EC TFEB in cardiac dysfunction under chemotherapy could provide new insight into the mechanisms underlying EC-cardiomyocyte communication in the heart.