Geng Y J, Libby P
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Am J Pathol. 1995 Aug;147(2):251-66.
This study sought evidence for apoptosis, a form of programmed cell death, in human atheromatous coronary and carotid arteries. Markers for apoptotic cells included in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), genomic DNA electrophoresis, and morphological analysis. Intimal lesions contained more TUNEL+ cells (34 +/- 6%, n = 8) than non-atherosclerotic arterial intima (8 +/- 3%, n = 5, P < 0.05). The tunica media of the diseased arteries had a percentage of TUNEL+ cells (5 +/- 1%) similar to that in the normal vessels (3 +/- 1%, N.S.). Oligonucleosomal DNA fragments were visualized in extracts from 12 atheromatous plaques but in none of 5 non-atherosclerotic vessels. Both smooth muscle cells (SMC) and macrophages, two major cell types in the atherosclerotic intima, bore markers of apoptosis, but with different patterns, as determined by double histochemical labeling for cell types and TUNEL. The TUNEL+ SMC localized mainly in the fibrotic portion of the atheroma, whereas TUNEL+ macrophages clustered near or within the lipid-rich core of the lesion. Atheromatous lesions expressed mRNA encoding interleukin-1 beta-converting enzyme (ICE), a mammalian cell death gene, as demonstrated by reverse transcriptase polymerase chain reaction. Immunohistochemistry revealed that ICE localized in regions of TUNEL+ SMC and macrophages. TUNEL- cells showed little or no immunoreactive ICE. These data point to a role for apoptosis in regulation of cell accumulation during atherogenesis and suggest involvement of ICE in SMC death in fibrous regions of complex atheroma, and in macrophage death in the lipid-rich core of the lesion. Apoptosis of vascular cells in fibrous cap may impede maintenance or repair of the matrix in this region and affect stability of the plaques.
本研究旨在寻找人类动脉粥样硬化性冠状动脉和颈动脉中凋亡（一种程序性细胞死亡形式）的证据。凋亡细胞的标志物包括原位末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法（TUNEL）、基因组DNA电泳和形态学分析。内膜病变中TUNEL阳性细胞（34±6%，n = 8）比非动脉粥样硬化动脉内膜（8±3%，n = 5，P < 0.05）更多。病变动脉的中膜TUNEL阳性细胞百分比（5±1%）与正常血管（3±1%，无显著性差异）相似。在12个动脉粥样硬化斑块的提取物中可见寡核小体DNA片段，而5个非动脉粥样硬化血管中均未见到。动脉粥样硬化内膜中的两种主要细胞类型，即平滑肌细胞（SMC）和巨噬细胞，均带有凋亡标志物，但模式不同，这是通过细胞类型和TUNEL的双重组织化学标记确定的。TUNEL阳性的SMC主要定位于动脉粥样硬化斑块的纤维化部分，而TUNEL阳性的巨噬细胞聚集在病变富含脂质核心的附近或内部。逆转录聚合酶链反应表明，动脉粥样硬化病变表达编码白细胞介素-1β转化酶（ICE，一种哺乳动物细胞死亡基因）的mRNA。免疫组织化学显示，ICE定位于TUNEL阳性的SMC和巨噬细胞区域。TUNEL阴性细胞几乎没有或没有免疫反应性ICE。这些数据表明凋亡在动脉粥样硬化形成过程中细胞积聚的调节中起作用，并提示ICE参与了复杂动脉粥样硬化斑块纤维区域的SMC死亡以及病变富含脂质核心区域的巨噬细胞死亡。纤维帽中血管细胞的凋亡可能会阻碍该区域基质的维持或修复，并影响斑块的稳定性。
