RESEARCH—LABORATORY

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

Kurki, Mitja I MSc*‡§; Häkkinen, Sanna-Kaisa MSc*¶; Frösen, Juhana MD, PhD‖; Tulamo, Riikka MD‖; von und zu Fraunberg, Mikael MD, PhD#; Wong, Garry PhD‡§; Tromp, Gerard PhD**; Niemelä, Mika MD, PhD#; Hernesniemi, Juha MD, PhD#; Jääskeläinen, Juha E MD, PhD‖; Ylä-Herttuala, Seppo MD, PhD

Author Information

‡Laboratory of Functional Genomics and Bioinformatics, Department of Neurobiology, §Department of Biosciences, and ¶Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland; ‖Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland; #Department of Neurosurgery, Helsinki University Hospital, Helsinki, Finland; **Center for Molecular Medicine and Genetics and Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan; Current address: Weis Center for Research, Geisinger Health System, Danville, Pennsylvania

Received, April 9, 2010.

Accepted, October 29, 2010.

*These authors have contributed equally to this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.neurosurgery-online.com).

Correspondence: Juha E. Jääskeläinen, MD, PhD, Professor, Chairman, Department of Neurosurgery, Kuopio University Hospital, PO Box 1777, 70 211 Kuopio, Finland. E-mail [email protected]

Neurosurgery 68(6):p 1667-1676, June 2011. | DOI: 10.1227/NEU.0b013e318210f001

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.

CONCLUSION: 

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.

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