Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, P.O. Box700, Haartmaninkatu 8, FI-00290, Helsinki, Finland.
J Mol Med (Berl). 2011 Oct;89(10):1015-26. doi: 10.1007/s00109-011-0773-z. Epub 2011 May 24.
Atherosclerotic carotid stenosis is an important risk factor for stroke. Carotid plaques (CPs) causing stroke may present a distinct type of molecular pathology compared with transient ischemic attack (TIA)-associated or asymptomatic plaques. We compared the gene expression profiles of CPs from stroke patients (n = 12) and asymptomatic patients (n = 9), both with similar risk factors and severity of carotid stenosis (>70%). Sixty probes showed over 1.5-fold expression difference at 5% false discovery rate. Functional clustering showed enrichment of genes in 51 GO categories and seven pathways, the most significant of which relate to extracellular-matrix interaction, PPAR gamma signaling, scavanger receptor activity, and lysosomal activity. Differential expression of ten genes was confirmed in an extended replication group (n = 43), where the most significant expression differences were found in CD36 (2.1-fold change, p = 0.005), CD163 (1.7-fold change, p = 0.007) and FABP4 (2.2-fold change, p = 0.015). These include four genes not previously linked to plaque destabilization: GLUL (2.2-fold change, p = 0.016), FUCA1 (2.2-fold change, p = 0.025), IL1RN (1.6-fold change, p = 0.034), and S100A8 (2.5-fold change, p = 0.047). Strong correlations were found to plaque ulceration, plaque hemorrhage, and markers of apoptosis and proliferation (activated caspase 3, TUNEL, and Ki67). Protein expression of these genes was confirmed by immunohistochemistry and was found in the atheromatous areas of CPs critical for plaque destabilization. This study presents a comprehensive transcriptional analysis of stroke-associated CPs and demonstrates a significant transcriptome difference between stroke-associated and asymptomatic CPs. Follow-up studies on the identified genes are needed to define whether they could be used as biomarkers of symptomatic CPs or have a role in plaque destabilization.
动脉粥样硬化性颈动脉狭窄是中风的一个重要危险因素。与短暂性脑缺血发作（TIA）相关或无症状斑块相比，导致中风的颈动脉斑块（CPs）可能表现出明显不同的分子病理学特征。我们比较了中风患者（n=12）和无症状患者（n=9）的 CPs 的基因表达谱，两者均具有相似的颈动脉狭窄风险因素和严重程度（>70%）。在 5%的假发现率下，有 60 个探针显示表达差异超过 1.5 倍。功能聚类显示，在 51 个 GO 类别和 7 个途径中有丰富的基因，其中最重要的与细胞外基质相互作用、PPARγ信号转导、清道夫受体活性和溶酶体活性有关。在一个扩展的复制组（n=43）中，10 个基因的差异表达得到了证实，其中 CD36（2.1 倍变化，p=0.005）、CD163（1.7 倍变化，p=0.007）和 FABP4（2.2 倍变化，p=0.015）的表达差异最显著。其中包括四个以前与斑块不稳定无关的基因：GLUL（2.2 倍变化，p=0.016）、FUCA1（2.2 倍变化，p=0.025）、IL1RN（1.6 倍变化，p=0.034）和 S100A8（2.5 倍变化，p=0.047）。与斑块溃疡、斑块出血以及细胞凋亡和增殖的标志物（活化的 caspase 3、TUNEL 和 Ki67）之间存在很强的相关性。通过免疫组织化学证实了这些基因的蛋白质表达，并在对斑块不稳定至关重要的 CPs 的动脉粥样硬化区域发现了这些基因的蛋白质表达。本研究对中风相关 CPs 进行了全面的转录分析，并证明了中风相关 CPs 和无症状 CPs 之间存在显著的转录组差异。需要对鉴定出的基因进行后续研究，以确定它们是否可作为有症状 CPs 的生物标志物，或在斑块不稳定中起作用。
