Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function.
Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function.
复制标题
Anthracycline心肌病是通过心脏干细胞池的耗竭介导的，并通过恢复祖细胞功能而挽救。
DOI：
10.1161/circulationaha.109.895771
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发表时间：
2010-01-19
期刊：
影响因子：
37.8
通讯作者：
Anversa P
中科院分区：
文献类型：
--
作者：
De Angelis A;Piegari E;Cappetta D;Marino L;Filippelli A;Berrino L;Ferreira-Martins J;Zheng H;Hosoda T;Rota M;Urbanek K;Kajstura J;Leri A;Rossi F;Anversa P
蒽环类药物是目前治疗肿瘤疾病最有效的药物。然而，它们对心脏的结构和功能有深远的影响，随着时间的推移，会导致心肌病，导致充血性心力衰竭。给大鼠注射阿霉素(Doxo)会导致扩张性肌病、心力衰竭和死亡。为了验证Doxo对心脏解剖和功能的影响是否通过心脏前体细胞的改变而介导，将这些细胞暴露于蒽环类药物，这些细胞增加了活性氧物种(ROS)的形成、DNA损伤、P53表达、端粒磨损和细胞凋亡。此外，Doxo导致细胞周期停滞于G2/M期，导致CPC生长显著下降。Doxo可诱导多种分子适应；在对存活的CPC池施加蒽环类药物的情况下，CCs发生大量的凋亡性死亡，激活了几条旨在保护原始状态、细胞分裂、谱系分化和修复受损DNA的途径。为了确定同基因祖细胞的输送是否能对抗Doxo心脏毒性的进展，将EGFP标记的CPC注射到衰竭的心肌中，这种治疗促进了心肌细胞和血管结构的再生，改善了心脏性能和动物存活率。我们的结果增加了这样一种可能性，即在给癌症患者服用抗肿瘤药物之前，可以获得自体CPC，然后给那些对这些药物的心脏毒性特别敏感的个人进行心力衰竭的预防和/或管理。
Anthracyclines are the most effective drugs available in the treatment of neoplastic diseases. However, they have profound consequences on the structure and function of the heart causing with time a cardiomyopathy that leads to congestive heart failure. Administration of doxorubicin (DOXO) in rats led to a dilated myopathy, heart failure and death. To test whether DOXO effects on cardiac anatomy and function were mediated by alterations in cardiac progenitor cells (CPCs), these cells were exposed to the anthracycline which increased the formation of reactive oxygen species (ROS), DNA damage, expression of p53, telomere attrition and apoptosis. Additionally, DOXO resulted in cell cycle arrest at the G2/M transition leading to a significant decrease in CPC growth. DOXO elicited multiple molecular adaptations; the massive apoptotic death occurring in CPCs in the presence of the anthracycline imposed on the surviving CPC pool the activation of several pathways aiming at the preservation of the primitive state, cell division, lineage differentiation and repair of damaged DNA. To establish whether delivery of syngeneic progenitor cells opposed the progression of DOXO cardiotoxicity, EGFP-labeled CPCs were injected in the failing myocardium and this treatment promoted regeneration of cardiomyocytes and vascular structures, improving ventricular performance and animal survival. Our results raise the possibility that autologous CPCs can be obtained before antineoplastic drugs are given to cancer patients and subsequently administrated to individuals who are particularly sensitive to the cardiotoxicity of these agents for prevention and/or management of heart failure.