A mechanistic role for cardiac myocyte apoptosis in heart failure
A mechanistic role for cardiac myocyte apoptosis in heart failure
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DOI：
10.1172/jci200317664
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发表时间：
2003-05-01
影响因子：
15.9
通讯作者：
Kitsis, RN
中科院分区：
文献类型：
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作者：
Wencker, D;Chandra, M;Kitsis, RN
心力衰竭是一种常见的致命疾病，其发病机制尚不清楚。最近的研究已经确定了在衰竭的人类心脏中低水平的肌细胞凋亡（每10（5）个核80-250个肌细胞）。然而，目前尚不清楚这种细胞死亡是巧合发现、保护过程还是发病机制中的因果成分。使用只在心肌中表达条件活性半胱天冬酶的转基因小鼠，我们证明了非常低水平的心肌细胞凋亡（每10（5）个核中有23个心肌细胞，而对照组中每105个核中有1.5个心肌细胞）足以引起致命的扩张型心肌病。有趣的是，这些水平比在衰竭的人类心脏中观察到的水平低四到十倍。相反，在该鼠模型中抑制心肌细胞死亡在很大程度上防止了心脏扩张和收缩功能障碍的发展，这是心力衰竭的标志。据我们所知，这些数据提供了第一个直接证据，心肌细胞凋亡可能是心力衰竭的一个因果机制，他们建议，抑制这种细胞死亡过程可能构成新的治疗方法的基础。
Heart failure is a common, lethal condition whose pathogenesis is poorly understood. Recent studies have identified low levels of myocyte apoptosis (80-250 myocytes per 10(5) nuclei) in failing human hearts. It remains unclear, however, whether this cell death is a coincidental finding, a protective process, or a causal component in pathogenesis. Using transgenic mice that express a conditionally active caspase exclusively in the myocardium, we demonstrate that very low levels of myocyte apoptosis (23 myocytes per 10(5) nuclei, compared with 1.5 myocytes per 105 nuclei in controls) are sufficient to cause a lethal, dilated cardiomyopathy. Interestingly, these levels are four- to tenfold lower than those observed in failing human hearts. Conversely, inhibition of cardiac myocyte death in this murine model largely prevents the development of cardiac dilation and contractile dysfunction, the hallmarks of heart failure. To our knowledge, these data provide the first direct evidence that myocyte apoptosis may be a causal mechanism of heart failure, and they suggest that inhibition of this cell death process may constitute the basis for novel therapies.