Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm

Abstract

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 Krüppel-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.

Serum Calcium is Related to the Degree of Artery Stenosis in Acute Ischemic Stroke

“…Then, the log2 fold-change was calculated. The raw P-values were adjusted into a false discovery rate (FDR) using the Benjamin and Hochberg method [18], which avoided too many false positive results due to the multi-test problem. Then FDR < 0.05 and |log 2 Fold Change (FC) |> 1 were used as the cut-off criteria to identify the ultimate DEGs.…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…TLR-6 that forms heterodimers with TLR-2, was also significantly overexpressed, ultimately suggesting this pro-inflammatory signaling pathway is involved in IA wall inflammation and rupture. [43] Finally, Krüppel-like transcription factors (KLF) KLF-2, KLF-12, and KLF-15 were all down-regulated in the early ruptured IA subgroup. KLF-2 is known to possess anti-inflammatory functionality.…”

“…To tackle the problem of biological heterogeneity among sample aneurysms, Nakaoka et al [43] determined the gene expression levels in 8 ruptured cerebral arteries (within 24 h post SAH), 5 unruptured cerebral aneurysms, and 10 control aneurysms (superficial temporal arteries) utilizing agilent microarrays. Critically, utilizing hierarchical clustering and nonnegative matrix factorization, the samples were classified into homogeneous subgroups showing similar gene expression patterns.…”

Presence of inflammatory proteins S100A8 and S100A9 in a giant intracranial aneurysm after flow diverter treatment

“…1 S100A8 and S100A9 expression can be induced upon activation in endothelial cells, vascular smooth muscle cells (VSMC) and fibroblasts. S100A8 and S100A9 expression amplifies the vascular inflammatory reaction by activating the vascular endothelium, inducing proliferation of VSMCs to the synthetic cell type and promoting further influx of leukocytes by the release of cytokines and chemokines.…”