Overexpression of copper-zinc superoxide dismutase attenuates acute activation of activator protein-1 after transient focal cerebral ischemia in mice

Citation
Cy. Huang et al., Overexpression of copper-zinc superoxide dismutase attenuates acute activation of activator protein-1 after transient focal cerebral ischemia in mice, STROKE, 32(3), 2001, pp. 741-747
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurology,"Cardiovascular & Hematology Research
Journal title
STROKE
ISSN journal
0039-2499 → ACNP
Volume
32
Issue
3
Year of publication
2001
Pages
741 - 747
Database
ISI
SICI code
0039-2499(200103)32:3<741:OOCSDA>2.0.ZU;2-2
Abstract
Background and Purpose-Reactive oxygen species (ROS) have been implicated i n reperfusion injury after focal cerebral ischemia (FCI). ROS are known to regulate the activity of transcription factors such as activator protein-1 (AP-1), which is a dimer consisting of members of the Jun and Fos families. We investigated the role of ROS in AP-1 activity after FCI using transgeni c mice that overexpressed copper-zinc superoxide dismutase (SOD1) and that had reduced infarction volume after FCI. Methods-The SOD1 transgenic mice and their wild-type littermates were subje cted to middle cerebral artery occlusion and reperfusion by intraluminal su ture blockade. After 60 minutes of middle cerebral artery occlusion, mice w ere allowed to recover for 1, 2, and 4 hours before euthanasia. Protein exp ression of c-Jun and c-Fos was examined by immunohistochemistry and Western blotting. AP-1 DNA-protein binding activity was assessed by electrophoreti c mobility shirt assays. Results-In wild-type mice, immunohistochemistry demonstrated acute c-Jun an d c-Fos activation in ischemic cortex and its outer boundary. Expression of both was reduced in SOD1 transgenic mice. Western blotting confirmed that SOD1 overexpression was associated with reduced c-Jun and c-Fos protein lev els in ischemic brain. Electrophoretic mobility shift assays revealed that the ischemia-enhanced DNA binding activity observed in wild-type mice was r educed in SOD1 transgenic mice. Supershift assays indicated that c-Jun part icipated in the bound AP-1 complex. Conclusions-SOD1 overexpression prevents early activation of AP-1 after tra nsient FCI in mice. This may block the expression of downstream target gene s that are injurious, thereby reducing the infarction volume after transien t FCI in mice.