Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm
Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm
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DOI：
10.1161/strokeaha.114.005851
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发表时间：
2014-08-01
期刊：
影响因子：
8.3
通讯作者：
Inoue, Ituro
中科院分区：
文献类型：
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作者：
Nakaoka, Hirofumi;Tajima, Atsushi;Inoue, Ituro
背景与目的：颅内动脉瘤破裂引起的蛛网膜下腔出血具有很高的发病率和死亡率。我们比较了未破裂的IAs和破裂的IAs （ria）在动脉瘤圆顶中的基因表达谱，以阐明易导致IA破裂的生物学机制。方法：采用安捷伦微阵列检测8例ria、5例未破裂IAs和10例颞浅动脉的基因表达水平。为了探索IAs的生物学异质性，我们使用聚类方法将样本分为具有相似基因表达模式的亚组。结果聚类分析确定了4组：颞浅动脉和未破裂动脉聚集在各自的聚类中，而ria则分为2个不同的亚组（早期和晚期ria）。通过比较早期ria和未破裂IAs的基因表达水平，我们在早期ria中鉴定出430个上调基因和617个下调基因。上调的基因与炎症和免疫反应以及吞噬有关，包括S100/calgranulin基因（S100A8、S100A9和S100A12）。下调的基因表明动脉瘤壁存在机械缺陷。抗炎调节因子Kruppel-like家族转录因子（KLF2、KLF12和KLF15）和IA全基因组关联研究中复制最一致的染色体9p21上的CDKN2A的表达也下调。结论：我们发现RIAs的基因表达模式随患者年龄的不同而不同。结果表明，巨噬细胞介导的炎症是IA破裂的关键生物学途径。所鉴定的基因可以作为易破裂IAs的分子标记和治疗靶点的良好候选者。
Background and Purpose-The rupture of intracranial aneurysm (IA) causes subarachnoid hemorrhage associated with high morbidity and mortality. We compared gene expression profiles in aneurysmal domes between unruptured IAs and ruptured IAs (RIAs) to elucidate biological mechanisms predisposing to the rupture of IA.Methods-We determined gene expression levels of 8 RIAs, 5 unruptured IAs, and 10 superficial temporal arteries with the Agilent microarrays. To explore biological heterogeneity of IAs, we classified the samples into subgroups showing similar gene expression patterns, using clustering methods.Results-The clustering analysis identified 4 groups: superficial temporal arteries and unruptured IAs were aggregated into their own clusters, whereas RIAs segregated into 2 distinct subgroups (early and late RIAs). Comparing gene expression levels between early RIAs and unruptured IAs, we identified 430 upregulated and 617 downregulated genes in early RIAs. The upregulated genes were associated with inflammatory and immune responses and phagocytosis including S100/calgranulin genes (S100A8, S100A9, and S100A12). The downregulated genes suggest mechanical weakness of aneurysm walls. The expressions of Kruppel-like family of transcription factors (KLF2, KLF12, and KLF15), which were anti-inflammatory regulators, and CDKN2A, which was located on chromosome 9p21 that was the most consistently replicated locus in genome-wide association studies of IA, were also downregulated.Conclusions-We demonstrate that gene expression patterns of RIAs were different according to the age of patients. The results suggest that macrophage-mediated inflammation is a key biological pathway for IA rupture. The identified genes can be good candidates for molecular markers of rupture-prone IAs and therapeutic targets.