title: Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factors.
abstract: BACKGROUND
  Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease.
  
  
  OBJECTIVE
  To investigate gene expression patterns distinguishing ruptured and unruptured sIA.
  
  
  METHODS
  We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes.
  
  
  RESULTS
  Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes.
  
  
  CONCLUSIONS
  We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.
authors.affiliation: Laboratory of Functional Genomics and Bioinformatics, Department of Neurobiology, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mitja I
authors.initials: MI
authors.lastname: Kurki
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Häkkinen
authors.forename: Juhana
authors.initials: J
authors.lastname: Frösen
authors.forename: Riikka
authors.initials: R
authors.lastname: Tulamo
authors.forename: Mikael
authors.initials: M
authors.lastname: von und zu Fraunberg
authors.forename: Garry
authors.initials: G
authors.lastname: Wong
authors.forename: Gerard
authors.initials: G
authors.lastname: Tromp
authors.forename: Mika
authors.initials: M
authors.lastname: Niemelä
authors.forename: Juha
authors.initials: J
authors.lastname: Hernesniemi
authors.forename: Juha E
authors.initials: JE
authors.lastname: Jääskeläinen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017542:Aneurysm, Ruptured / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D002532:Intracranial Aneurysm / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D050783:Proto-Oncogene Proteins c-ets; D051193:Toll-Like Receptors