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Although the early effects of doxorubicin-induced cardiotoxicity may be attributed to a direct effect on the cardiomyocytes, the mechanisms underlying the delayed or late effects (8\u201320 yr) are unknown. The goal of this project was to develop a model of late-onset doxorubicin-induced cardiotoxicity to better delineate the underlying pathophysiology responsible. The underlying hypothesis was that doxorubicin-induced \u201clate-onset cardiotoxicity\u201d was the result of mitochondrial dysfunction leading to cell failure and death. Wistar rats, 3\u20134 wk of age, were randomly assigned to vehicle or doxorubicin injection groups (1\u201345 mg\/kg). Cardiovascular function was unaltered at the lower dosages (1\u201315 kg\/mg), but beginning at 6 mo after injection significant cardiac degradation was observed in the 45 mg\/kg group. Doxorubicin significantly increased myocardial mitochondrial DNA (mtDNA) damage. In contrast, in isolated c-kit left ventricular (LV) cells, doxorubicin treatment did not increase mtDNA damage. Biomarkers of senescence within the LV were significantly increased, suggesting accelerated aging of the LV. Doxorubicin also significantly increased LV histamine content suggestive of mast cell activation. With the use of flow cytometry, a significant expansion of the c-kit and stage-specific embryonic antigen 1 cell populations within the LV were concomitant with significant decreases in the circulating peripheral blood population of these cells. These results are consistent with the concept that doxorubicin induced significant damage to the cardiomyocyte population and that although the heart attempted to compensate it eventually succumbed to an inability for self-repair.<\/jats:p>","DOI":"10.1152\/ajpcell.00073.2019","type":"journal-article","created":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T16:22:19Z","timestamp":1578500539000},"page":"C380-C391","source":"Crossref","is-referenced-by-count":89,"title":["Accelerated cardiomyocyte senescence contributes to late-onset doxorubicin-induced cardiotoxicity"],"prefix":"10.1152","volume":"318","author":[{"given":"Maria A.","family":"Mitry","sequence":"first","affiliation":[{"name":"Department of Physiology, New York Medical College, Valhalla, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri","family":"Laurent","sequence":"additional","affiliation":[{"name":"Department of Physiology, New York Medical College, Valhalla, New 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