Department of Cardiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Cardiovasc Res. 2012 Dec 1;96(3):456-65. doi: 10.1093/cvr/cvs282. Epub 2012 Sep 5.
Active autophagy has recently been reported in doxorubicin-induced cardiotoxicity; here we investigated its pathophysiological role.
Acute cardiotoxicity was induced in green fluorescent protein-microtubule-associated protein 1 light chain 3 (GFP-LC3) transgenic mice by administering two intraperitoneal injections of 10 mg/kg doxorubicin with a 3 day interval. A starvation group was deprived of food for 48 h before each injection to induce autophagy in advance. Doxorubicin treatment caused left ventricular dilatation and dysfunction within 6 days. Cardiomyocyte autophagy appeared to be activated in the doxorubicin group, based on LC3, p62, and cathepsin D expression, while it seemed somewhat diminished by starvation prior to doxorubicin treatment. Unexpectedly, however, myocardial ATP levels were reduced in the doxorubicin group, and this reduction was prevented by earlier starvation. Electron microscopy revealed that the autophagic process was indeed initiated in the doxorubicin group, as shown by the increased lysosomes, but was not completed, i.e. autophagolysosome formation was rare. Starvation prior to doxorubicin treatment partly restored autophagosome formation towards control levels. Autophagic flux assays in both in vivo and in vitro models confirmed that doxorubicin impairs completion of the autophagic process in cardiomyocytes. The activities of both AMP-activated protein kinase and the autophagy-initiating kinase unc-51-like kinase 1 (ULK1) were found to be decreased by doxorubicin, and these were restored by prior starvation.
Prior starvation mitigates acute doxorubicin cardiotoxicity; the underlying mechanism may be, at least in part, restoration and further augmentation of myocardial autophagy, which is impaired by doxorubicin, probably through inactivation of AMP-activated protein kinase and ULK1.
最近有报道称，多柔比星诱导的心脏毒性中存在活跃的自噬；本研究旨在探究其病理生理学作用。
通过给予 GFP-LC3 转基因小鼠两次腹腔注射 10mg/kg 多柔比星（间隔 3 天），建立急性心脏毒性模型。在每次注射前，饥饿组禁食 48h 以预先诱导自噬。多柔比星处理后 6 天内导致左心室扩张和功能障碍。基于 LC3、p62 和组织蛋白酶 D 的表达，多柔比星组的心肌自噬似乎被激活，而在多柔比星处理前饥饿则使其略有减少。然而，出乎意料的是，多柔比星组心肌 ATP 水平降低，而这种降低可通过早期饥饿来预防。电子显微镜显示，自噬过程确实在多柔比星组中被启动，表现为溶酶体增加，但未完成，即自噬溶酶体形成很少。多柔比星处理前的饥饿部分恢复了自噬体的形成，使其接近对照水平。在体内和体外模型中进行的自噬流测定均证实，多柔比星损害了心肌细胞中自噬过程的完成。多柔比星还降低了 AMP 激活的蛋白激酶和自噬起始激酶 UNC-51 样激酶 1（ULK1）的活性，而饥饿预处理则恢复了这些活性。
多柔比星预处理减轻了急性多柔比星心脏毒性；其潜在机制可能至少部分是通过恢复和进一步增强心肌自噬来实现的，而多柔比星则损害了自噬，可能通过 AMP 激活的蛋白激酶和 ULK1 的失活来实现。
