PT - JOURNAL ARTICLE AU - Philip Kawalec AU - Matthew D. Martens AU - Jared T. Field AU - Wajihah Mughal AU - Andrei Miguel Caymo AU - Donald Chapman AU - Bo Xiang AU - Saeid Ghavami AU - Vernon W. Dolinsky AU - Joseph W. Gordon TI - Differential Impact of Doxorubicin Dose on Cell Death and Autophagy Pathways during Acute Cardiotoxicity AID - 10.1101/2022.01.15.476450 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.01.15.476450 4099 - http://biorxiv.org/content/early/2022/01/18/2022.01.15.476450.short 4100 - http://biorxiv.org/content/early/2022/01/18/2022.01.15.476450.full AB - Doxorubicin (DOX) is an effective anthracycline used in chemotherapeutic regimens for a variety of haematological and solid tumors. However, its utility remains limited by its well-described, but poorly understood cardiotoxicity. Despite numerous studies describing various forms of regulated cell death and their involvement in DOX-mediated cardiotoxicity, the predominate form of cell death remains unclear. Part of this inconsistency lies in a lack of standardization of in vivo and in vitro model design. To this end, the objective of this study was to characterize acute low- and high-dose DOX exposure on cardiac structure and function in C57BL/6N mice, and evaluate regulated cell death pathways and autophagy both in vivo and in cardiomyocyte culture models. Acute low-dose DOX had little impact on cardiac structure or function; however, acute high-dose DOX elicited substantial cardiac necrosis resulting in diminished cardiac mass and volume, with a corresponding reduced cardiac output, and without impacting ejection fraction or fibrosis. Low-dose DOX consistently activated caspase-signaling with evidence of mitochondrial permeability transition. However, acute high-dose DOX had only modest impact on common necrotic signaling pathways, but instead led to an inhibition in autophagic flux. Intriguingly, when autophagy was inhibited in cultured cardiomyoblasts, DOX-induced necrosis was enhanced. Collectively, these observations implicate inhibition of autophagy flux as an important component of the acute necrotic response to DOX, but also suggest that acute high-dose DOX exposure does not recapitulate the disease phenotype observed in human cardiotoxicity.Competing Interest StatementThe authors have declared no competing interest.