Apoptotic versus autophagic cell death in heart failure
Apoptotic versus autophagic cell death in heart failure
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DOI：
10.1016/s0008-6363(01)00290-5
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发表时间：
2001-08-01
影响因子：
10.8
通讯作者：
Kockx, MM
中科院分区：
文献类型：
--
作者：
Knaapen, MWM;Davies, MJ;Kockx, MM
目的：心肌细胞进行性丢失是心力衰竭的重要病理特征之一。细胞凋亡可能是心力衰竭中细胞死亡的一种重要模式，但必须通过多种标准来证明，而不仅仅是TUNEL染色。以前，我们和其他人已经证明，除了细胞凋亡，其他现象，如活跃的基因转录可以导致TUNEL阳性。此外，其他类型的细胞死亡是半胱天冬酶独立的可能是重要的心力衰竭。本研究检验了TUNEL标记是否与半胱天冬酶激活平行的假设。研究方法：对缺血性心肌病（ICM）和扩张型心肌病（DCM）所致心力衰竭终末期患者的心脏组织进行了研究。以胎鼠心脏为阳性对照，检测经典凋亡。结果如下：在小鼠胚胎心脏，我们可以清楚地发现凋亡细胞死亡检测TUNEL标记和免疫组化的激活caspase-3。在心力衰竭中，TUNEL阳性心肌细胞对活性半胱天冬酶-3呈阴性，但显示出活性基因转录的迹象（SC-35）。然而，自噬细胞死亡可以在0.3%的心肌细胞中发现。自噬性细胞死亡表现为颗粒状细胞质泛素包涵体，这是神经元自噬作用的一个既定标志。有趣的是，这些自噬性心肌细胞是TUNEL和活化的半胱天冬酶-3阴性的，但也是阴性的C9，坏死的标志物。Western印迹分析证实，在心肌病中没有发生caspase-3和caspase-7的切割。结论：本研究证明了心脏组织中细胞死亡的两种根本不同的情况。在胚胎小鼠中，心肌细胞经历半胱天冬酶依赖性细胞死亡。然而，心力衰竭中的心肌细胞表现出半胱天冬酶非依赖性自噬细胞死亡，而不是凋亡性细胞死亡。(C)2001年，爱思唯尔科学。All rights reserved.
Objective: Progressive loss of cardiomyocytes is one of the most important pathogenic characteristics of heart failure. Apoptosis may be an important mode of cell death in heart failure but it must be demonstrated by multiple criteria and not just TUNEL staining alone. Previously, we and others have demonstrated that besides apoptosis other phenomena like active gene transcription can result in TUNEL positivity. Moreover, other types of cell death that are caspase-independent could be important in heart failure. This study examined the hypothesis whether TUNEL labeling parallels caspase activation. Methods: Cardiac tissue of patients in the terminal stage of heart failure as a consequence of ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) were studied. Embryonic mice hearts were used for positive control for detection of the classical apoptosis. Results: In mice embryonic hearts we could clearly find apoptotic cell death detected by TUNEL labeling and immunohistochemistry for activated caspase-3. In heart failure, TUNEL-positive cardiomyocytes were negative for active caspase-3 but showed signs of active gene transcription (SC-35). However, autophagic cell death could be found in 0.3% of the cardiomyocytes. Autophagic cell death was demonstrated by granular cytoplasmic ubiquitin inclusions, an established marker of autophagocytosis in neurons. Interestingly, these autophagic cardiomyocytes were TUNEL and activated caspase-3 negative but were also negative for C9, a marker for necrosis. Western blot analysis confirmed that in cardiomyopathies no cleavage of caspase-3 and caspase-7 occurred. Conclusion: The present study demonstrates two fundamentally different situations of cell death in cardiac tissue. In embryonic mice, cardiomyocytes undergo caspase-dependent cell death. However, cardiomyocytes in heart failure show caspase-independent autophagic cell death rather than apoptotic cell death. (C) 2001 Elsevier Science BY. All rights reserved.