Contribution of Endoplasmic Reticulum Stress to the Clinical Instability of Carotid Plaques in Human Carotid Stenosis
Contribution of Endoplasmic Reticulum Stress to the Clinical Instability of Carotid Plaques in Human Carotid Stenosis
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DOI：
10.1007/s12975-021-00968-4
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发表时间：
2021-11
影响因子：
6.9
通讯作者：
K. Hosoda;T. Imahori;Kazuhiro Tanaka;Takiko Uno;T. Nakai;M. Kohta;A. Fujita;T. Sasayama
中科院分区：
文献类型：
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作者：
K. Hosoda;T. Imahori;Kazuhiro Tanaka;Takiko Uno;T. Nakai;M. Kohta;A. Fujita;T. Sasayama
内质网应激是动脉粥样硬化进展过程中的一个重要过程。本研究的目的是阐明内质网应激与颈动脉斑块临床不稳定性的关系。193例颈动脉狭窄患者行颈动脉内膜剥脱术。我们将患者分为3组：无症状、有症状和CTIA(逐渐加重的短暂性脑缺血发作)/SIE(卒中进展)组。免疫组织化学染色检测内质网应激和细胞凋亡。采用Tukey-Kramer检验和有序Logistic回归分析ER应激标志物表达与临床不稳定性的关系。从193个CEA中随机选择24个无症状斑块和24个有症状斑块，CTIA/SIE组的7个斑块全部入选。糖蛋白A染色显示斑块内出血与临床不稳定性显著相关(优势比[OR]，1.27；95%CI，1.14~1.41)。内质网应激标志物(葡萄糖调节蛋白78[GRP78]和C/EBP同源蛋白[CHOP])的表达与临床不稳定性显著相关(GRP78：OR，1.25；95%CI，1.14~1.38；CHOP：OR，1.39；95%CI，1.16~1.66)。免疫荧光双标结果显示，CD68阳性细胞和SMA阳性细胞均可检测到ER应激标志物。ER应激标志物的共表达与临床不稳定性显著相关(CD6 8/GRP78：OR，1.13；95%CI，1.0 5~1.2 0，CD68/CHOP：OR，1.092；95%CI，1.0 4~1.14，SMA/CHOP：OR，1.082；95%CI，1.0 4~1.13)。然而，CHOP和切割的caspase-3(细胞凋亡标记物)的共存与临床不稳定性无关。这些发现表明，内质网应激通路可能是预防卒中的潜在治疗靶点。
Endoplasmic reticulum (ER) stress is an important process during the progression of atherosclerosis. The aim of this study was to elucidate the association of ER stress and clinical instability of carotid plaque. One hundred ninety-three patients with carotid stenosis undergoing carotid endarterectomies (CEAs) were enrolled. We classified the patients into 3 groups: the asymptomatic, symptomatic, and cTIA (crescendo transient ischemic attack)/SIE (stroke in evolution) groups. Immunohistological staining was performed to assess ER stress and apoptosis. The correlation between ER stress marker expression and clinical instability was analyzed by Tukey–Kramer test and ordinal logistic regression. From the 193 CEAs, 24 asymptomatic plaques and 24 symptomatic plaques were randomly selected, and all 7 plaques in the cTIA/SIE group were selected. Glycophorin A staining demonstrated significant correlation between intraplaque hemorrhage and clinical instability (odds ratio [OR], 1.27; 95%CI, 1.14–1.41). The expression of ER stress markers (glucose-regulated protein 78 [GRP78] and C/EBP homologous protein [CHOP]) exhibited a significant correlation with clinical instability (GRP78: OR, 1.25; 95%CI, 1.14–1.38, CHOP: OR, 1.39; 95%CI, 1.16–1.66). Double-label immunofluorescence demonstrated ER stress markers were detected in CD68-positive cells and smooth muscle actin (SMA)-positive cells. The coexpression of the ER stress markers exhibited a significant correlation with clinical instability (CD68/GRP78: OR, 1.13; 95%CI, 1.05–1.20, CD68/CHOP: OR, 1.092; 95%CI, 1.04–1.14, SMA/CHOP: OR, 1.082; 95%CI, 1.04–1.13). However, the colocalization of CHOP and cleaved caspase-3 (apoptosis marker) did not correlate with clinical instability. These findings indicated that the ER stress pathway may be a potential therapeutic target in the prevention of stroke.