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Oxidative Stress Is Associated With Cell Death, Wall Degradation, and Increased Risk of Rupture of the Intracranial Aneurysm Wall

Laaksamo, Elisa MD*; Tulamo, Riikka MD, PhD*; Liiman, Arto MB*; Baumann, Marc MB, PhD; Friedlander, Robert M. MD§,#; Hernesniemi, Juha MD, PhD*,¶; Kangasniemi, Marko MD, PhD*,‖; Niemelä, Mika MD, PhD*,¶; Laakso, Aki MD, PhD*,¶; Frösen, Juhana MD, PhD*,¶,#

doi: 10.1227/NEU.0b013e3182770e8c

BACKGROUND: The cause of rupture of intracranial aneurysms (IA) is not well understood. We previously demonstrated that loss of cells from the IA wall is associated with wall degeneration and rupture.

OBJECTIVE: To investigate the mechanisms mediating cell death in the IA wall.

METHODS: Snap-frozen tissue samples from aneurysm fundi were studied with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunostaining (14 unruptured and 20 ruptured), as well as with Western blot (12 unruptured and 12 ruptured).

RESULTS: Ruptured IA walls had more TUNEL-positive cells than unruptured walls (P < .001). Few cells positive for cleaved caspase-3 were detected. Cleaved caspase-9 (intrinsic activation of apoptosis) was significantly increased in ruptured IA walls, whereas cleaved caspase-8 (extrinsic activation of apoptosis) was not detected. Increased expression of hemeoxygenase-1, a marker for oxidative stress, was associated with IA wall degeneration and rupture.

CONCLUSION: Our results show that programmed cell death is activated in the IA wall via the intrinsic pathway. High oxidative stress in the IA wall is probably a significant cause of the intrinsic activation of cell death.

ABBREVIATIONS: AR, aspect ratio

αSMA, α-smooth muscle actin

HO-1, heme oxygenase-1

IA, intracranial aneurysm

SAH, subarachnoid hemorrhage

SMC, smooth muscle cell

TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling

WB, Western blotting

*Neurosurgery Research Group, Biomedicum Helsinki, and

Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland

Protein Chemistry/Proteomics Laboratory, Institute of Biomedicine, University of Helsinki, Helsinki, Finland

§Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

Department of Radiology, University of Helsinki and HUS Radiology (Medical Imaging Center), Helsinki, Finland

#Neuroapoptosis Laboratory, Harvard Medical School, Boston, Massachusetts

Correspondence: Juhana Frösen, MD, PhD, Department of Neurosurgery, Helsinki University Central Hospital, PO Box 266, 00029 HUS, Helsinki, Finland. E-mail:

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Received March 20, 2012

Accepted September 14, 2012

Copyright © by the Congress of Neurological Surgeons