Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death
Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death
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DOI：
10.1016/s0002-9440(10)64641-x
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发表时间：
2000-10-01
影响因子：
6
通讯作者：
Virmani, R
中科院分区：
文献类型：
--
作者：
Kolodgie, FD;Narula, J;Virmani, R
虽然细胞凋亡在慢性动脉粥样硬化性疾病中是一种公认的现象，但它在冠状动脉猝死，特别是急性斑块破裂中的作用尚不清楚，我们对40例冠状动脉猝死的罪魁祸首病变进行了评估。死亡机制分为两种：斑块破裂伴急性血栓形成(n=25)和稳定斑块伴或不伴心肌梗死愈合(n=15)。通过DNA片段化染色鉴定凋亡细胞，并结合金标记法和超微结构分析对部分病例进行鉴定。此外，还进行了其他研究，以检测两种凋亡诱导剂caspase-1和-3的表达和激活情况。斑块破裂表现为纤维帽内广泛的巨噬细胞浸润，尤其是在含有较少炎症细胞的稳定病变相反的部位。在罪魁祸首病变中，纤维帽的总凋亡率在破裂斑块中显著增加(P<；0.001)，并且主要定位于CD68阳性的巨噬细胞，此外，斑块破裂部位的AA变性比完整的纤维帽区域更常见(P=0.028)，斑块破裂部位对凋亡的巨噬细胞内的caspase-1有很强的免疫反应，caspase-3的染色很弱。对破裂斑块的免疫印迹分析显示caspase-1表达上调，其活性p20亚基的存在，而稳定的斑块仅显示前体；非动脉粥样硬化对照节段的前体和活性酶均为阴性，这些发现表明巨噬细胞广泛的凋亡局限于斑块破裂部位。Caspase-1在破裂斑块中的蛋白水解性裂解表明这一凋亡前体被激活。巨噬细胞凋亡是急性斑块破裂所必需的，还是对斑块破裂本身的一种反应仍有待确定。
Although apoptosis is a well-recognized phenomenon in chronic atherosclerotic disease, its role in sudden coronary death, in particular, acute plaque rupture is unknown, Culprit lesions from 40 cases of sudden coronary death were evaluated. Cases were divided into two mechanisms of death: ruptured plaques with acute thrombosis (n = 25) and stable plaques with and without healed myocardial infarction (n = 15). Apoptotic cells were identified by staining of fragmented DNA and confirmed in select cases by gold conjugate labeling combined with ultrastructural analysis. Additional studies were performed to examine the expression and activation of two inducers of apoptosis, caspases-1 and -3. Ruptured plaques showed extensive macrophage infiltration of the fibrous cap, in particular at rupture sites contrary to stable lesions, which contained fewer inflammatory cells, Among the culprit lesions, the overall incidence of apoptosis in fibrous caps was significantly greater in, ruptured plaques (P < 0.001) and was predominantly localized to the CD68-positive macrophages, Furthermore, aa optosis at plaque rupture sites was more frequent than in areas of intact fibrous cap (P = 0.028), Plaque rupture sites demonstrated a strong immunoreactivity to caspase-1 within the apoptotic macrophages; staining for caspase-3 was weak. Immunoblot analysis of ruptured plaques demonstrated caspase-1 upregulation and the presence of its active p20 subunit whereas stable lesions showed only the precursor; nonatherosclerotic control segments were negative for both precursor and active enzyme, These findings demonstrate extensive apoptosis of macrophages limited to the site of plaque rupture. The proteolytic cleavage of caspase-1 In ruptured plaques suggests activation of this apoptotic precursor. whether macrophage apoptosis is essential to acute plaque rupture or is a response to the rupture itself remains to be determined.