Increased inflammation and brain injury after transient focal cerebral ischemia in activating transcription factor 3 knockout mice.
OBJECTIVE
Activating transcription factor 3 (ATF3) is a stress-induced transcription factor that has been shown to repress inflammatory gene expression in multiple cell types and diseases. This study was conducted to investigate the role of ATF3 in the pathological processes of cerebral ischemia and its influence on post-ischemic inflammation.


METHODS
Wild-type (WT) and ATF3 knockout (KO) mice were subjected to middle cerebral artery occlusion (45 min) followed by reperfusion. Infarct volume, brain edema, and neurological deficits were examined. Neural apoptosis, inflammatory gene expression, cellular inflammatory response and Matrix Metallo Proteinases 9 (MMP9) activity were assessed. Activity of the nuclear factor-kappa B (NF-κB) signaling pathway and cAMP-responsive element-binding protein (CREB) was studied.


RESULTS
Knockout of ATF3 significantly exacerbated the infarct volume and worsened neurological function after brain ischemia. Neural apoptosis, inflammatory gene expression and cellular inflammatory response were upregulated in ATF3 KO mice. The MMP9 mRNA expression and protein activity were increased in ATF3 KO mice. KO of ATF3 led to an elevation in the activity of the NF-κB signaling pathway and inhibition of CREB activity.


CONCLUSIONS
Our study demonstrated that ATF3 was markedly induced by brain ischemia. ATF3 deficiency exacerbated the inflammatory response and brain injury after cerebral ischemia, potentially through further activation of the NF-κB signaling pathway. ATF3 is likely an important protective regulator in cerebral ischemic injury.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
L
L
Wang
S
S
Deng
Y
Y
Lu
Y
Y
Zhang
L
L
Yang
Y
Y
Guan
H
H
Jiang
H
H
Li
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse