Department of Cellular and Integrative Physiology, University of Texas Health Science Center San Antonio, San Antonio, TX, United States of America.
Greehey Children's Cancer Research Institute, University of Texas Health Science Center San Antonio, San Antonio, TX, United States of America.
PLoS One. 2020 Sep 22;15(9):e0238856. doi: 10.1371/journal.pone.0238856. eCollection 2020.
Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.
蒽环类药物由于其广泛的抗癌疗效，是大多数儿科化疗方案的关键组成部分。不幸的是，绝大多数长期儿童癌症幸存者都会因成功治疗而患上慢性健康疾病，严重的心脏病是一种常见的危及生命的后果，与之前的蒽环类药物暴露明确相关。蒽环类药物（如阿霉素）如何损害心脏并引发一个在几十年中进展的疾病过程，其机制尚未完全了解。一个很大程度上尚未研究的领域是心脏成纤维细胞的作用，心脏成纤维细胞是心脏成熟和损伤反应的关键细胞类型。在这项研究中，我们证明了在存在和不存在关键的 DNA 损伤反应蛋白 p53 的情况下，阿霉素对心脏成纤维细胞功能的影响。在野生型心脏成纤维细胞中，阿霉素诱导的损伤与增殖和迁移减少、细胞周期停滞以及扩张型心肌病基因表达谱相关。有趣的是，这些阿霉素诱导的变化在 p53-/-心脏成纤维细胞中完全或部分恢复。此外，在野生型心脏成纤维细胞中，阿霉素产生 DNA 损伤和线粒体功能障碍，这两者都是细胞毒性化疗和各种形式的心脏损伤引起的典型细胞应激反应。p53 增加 3 倍（p = 0.004）通过隔离 Parkin 阻止了自噬体的完成（p = 0.032）。阿霉素处理的心脏成纤维细胞中 p53 和 Parkin 之间的相互作用增加（p = 0.0003）。最后，Parkin 无法在野生型心脏成纤维细胞中定位到线粒体，但在 p53-/-心脏成纤维细胞中恢复了线粒体定位。这些发现强烈表明心脏成纤维细胞是一种重要的心肌细胞类型，值得在阿霉素治疗的背景下进一步研究。更深入地了解心脏成纤维细胞在阿霉素诱导的心脏毒性发展中的作用将导致新的临床策略，从而提高癌症幸存者的生活质量。
