The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress
The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress
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DOI：
10.1038/nm1574
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发表时间：
2007-05-01
期刊：
影响因子：
82.9
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
--
作者：
Nakai, Atsuko;Yamaguchi, Osamu;Otsu, Kinya
自噬是细胞质组分大量降解的进化保守过程，是饥饿细胞中的细胞存活机制（1，2）。虽然在各种心脏疾病中观察到了改变的自噬，包括心脏肥大（3，4）和心力衰竭（5，6），但尚不清楚自噬在心脏中是否起着有益或有害的作用。在这里，我们报告了心脏特异性自噬丧失导致小鼠心肌病。在成年小鼠中，Atg 5（自噬相关5）（自噬所需的蛋白质）的时间控制心脏特异性缺陷导致心脏肥大，左心室扩张和收缩功能障碍，伴随着泛素化水平的增加。此外，Atg5缺陷的心脏表现出紊乱的肌节结构和线粒体错位和聚集。另一方面，心脏发育早期心脏特异性Atg5缺乏在基线条件下没有显示出这样的心脏表型，但在压力超负荷治疗后一周出现心功能不全和左心室扩张。这些结果表明，在基线条件下心脏中的组成性自噬是维持心肌细胞大小和整体心脏结构和功能的稳态机制，并且衰竭心脏中自噬的上调是保护细胞免受血液动力学应激的适应性反应。
Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells(1,2). Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy(3,4) and heart failure(5,6), it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.