Resistance to fas-induced apoptosis in cells from human atherosclerotic lesions: elevated Bcl-XL inhibits apoptosis and caspase activation.
Resistance to fas-induced apoptosis in cells from human atherosclerotic lesions: elevated Bcl-XL inhibits apoptosis and caspase activation.
复制标题
抵抗人动脉粥样硬化病变细胞中 fas 诱导的细胞凋亡：Bcl-XL 升高可抑制细胞凋亡和 caspase 激活。
DOI：
10.1159/000106466
复制
发表时间：
2007
影响因子：
1.7
通讯作者：
McCaffrey,TimothyA
中科院分区：
文献类型：
--
作者：
Yang,Zhaoqing;Gagarin,Dmitry;Ramezani,Ali;Hawley,RobertG;McCaffrey,TimothyA
新生内膜中细胞的不适当存活有助于动脉粥样硬化斑块的进展，而病变纤维帽中的细胞凋亡有助于心肌梗死和中风。先前的基因组水平的人类颈动脉斑块细胞的转录谱，已知的敏感性或耐Fas诱导的细胞凋亡，确定候选基因参与病变细胞凋亡。逆转录病毒的过度表达表明，几个候选因素不是致病的，但Bcl-XL赋予完全抵抗Fas连接诱导的细胞凋亡。抗性细胞不能有效地激活半胱天冬酶8，在Bcl-XL转染的细胞中也观察到这种效应。小分子Bcl-2/XL抑制剂和Bcl-XL的siRNA敲低显著地使抗性细胞对凋亡敏感，并且部分地恢复caspase 8活化。Caspase 3、6和9抑制剂降低Caspase 8活化并阻断凋亡。半胱天冬酶9的完全敲除没有减少细胞凋亡，而Bid的敲除抑制细胞凋亡，这表明不依赖于半胱天冬酶9的线粒体途径，如Smac/Diablo或AIF，为有效的半胱天冬酶激活提供了必要的线粒体输入。Bcl-XL似乎通过抑制caspase激活环的线粒体扩增来调节损伤细胞的凋亡。这些结果可能对控制斑块不稳定性/进展有直接影响，并确定了一类新的小分子来抑制再狭窄。
The inappropriate survival of cells in the neointima contributes to atherosclerotic plaque progression, while apoptosis in the fibrous cap of lesions contributes to myocardial infarction and stroke. Prior genomic-scale transcript profiling of human carotid artery plaque cells with known sensitivity or resistance to fas-induced apoptosis identified candidate genes involved in lesion cell apoptosis. Retroviral overexpression indicated that several candidate factors were not causative, but that Bcl-X L conferred complete resistance to apoptosis induced by fas ligation. Resistant cells failed to efficiently activate caspase 8, an effect which was also observed in Bcl-X L-transfected cells. Small-molecule Bcl-2/X L inhibitors and siRNA knockdown of Bcl-X L markedly sensitized resistant cells to apoptosis, and partially restored caspase 8 activation. Caspase 3, 6 and 9 inhibitors reduced caspase 8 activation and blocked apoptosis. Complete knockdown of caspase 9 did not reduce apoptosis, while knockdown of Bid suppressed apoptosis, suggesting that mitochondrial pathways independent of caspase 9, such as Smac/Diablo or AIF, provide a necessary mitochondrial input to efficient caspase activation. Bcl-X L appears to modulate lesion cell apoptosis by suppressing mitochondrial amplification of caspase activation loops. The results may have direct implications for controlling plaque instability/progression, and identify a new class of small molecules to inhibit restenosis.