Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and vascularization resulting in greater susceptibility to stress-induced myocardial injury in adult mice.
Juvenile exposure to anthracyclines impairs cardiac progenitor cell function and vascularization resulting in greater susceptibility to stress-induced myocardial injury in adult mice.
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DOI：
10.1161/circulationaha.109.902221
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发表时间：
2010-02-09
期刊：
影响因子：
37.8
通讯作者：
Gustafsson AB
中科院分区：
文献类型：
--
作者：
Huang C;Zhang X;Ramil JM;Rikka S;Kim L;Lee Y;Gude NA;Thistlethwaite PA;Sussman MA;Gottlieb RA;Gustafsson AB
蒽环类多柔比星（DOX）是一种用于治疗儿科癌症的有效化疗药物，但与心脏毒性相关，可在首次暴露后多年表现出来。迄今为止，对这种迟发性心脏毒性的机制知之甚少。为了理解这个问题，我们开发了迟发性DOX诱导的心脏毒性的儿科模型，其中幼年小鼠暴露于DOX，使用不诱导急性心脏毒性的累积剂量。这些小鼠发育正常，成年后没有明显的心脏异常。然而，血管系统的评价显示，幼年DOX暴露损害血管发育，导致心脏中的异常血管结构，具有较少的分支和降低的毛细血管密度。生理和病理应激均可诱导成年DOX小鼠的迟发性心脏毒性。此外，心肌梗死（MI）的成年小鼠出现快速心力衰竭，这与未能增加受伤区域的毛细血管密度有关。祖细胞参与MI后的再生和血管形成，但DOX小鼠在梗死边缘区的祖细胞较少。有趣的是，DOX处理减少了祖细胞向心脏谱系细胞的增殖和分化。我们的数据表明，蒽环类药物治疗损害了年轻心脏的血管发育和祖细胞功能，导致成年心脏更容易受到压力的影响。
The anthracycline doxorubicin (DOX) is an effective chemotherapeutic agent used to treat pediatric cancers, but is associated with cardiotoxicity which can manifest many years after the initial exposure. To date, very little is known about the mechanism of this late onset cardiotoxicity. To understand this problem, we developed a pediatric model of late onset DOX-induced cardiotoxicity, where juvenile mice were exposed to DOX, using a cumulative dose that did not induce acute cardiotoxicity. These mice developed normally and had no obvious cardiac abnormalities as adults. However, evaluation of the vasculature revealed that juvenile DOX exposure impaired vascular development resulting in abnormal vascular architecture in the hearts with less branching and decreased capillary density. Both physiological and pathological stress induced late onset cardiotoxicity in the adult DOX mice. Moreover, adult mice subjected to myocardial infarction (MI) developed rapid heart failure which correlated with a failure to increase capillary density in the injured area. Progenitor cells participate in regeneration and blood vessel formation after an MI, but DOX mice had fewer progenitor cells in the infarct border zone. Interestingly, DOX treatment reduced proliferation and differentiation of the progenitor cells into cells of cardiac lineages. Our data suggest that anthracycline treatment impairs vascular development as well as progenitor cell function in the young heart, resulting in an adult heart that is more susceptible to stress.