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ATM gene regulates oxygen-glucose deprivation-induced nuclear factor-kappaB DNA-binding activity and downstream apoptotic cascade in mouse cerebrovascular endothelial cells.

Abstract：

BACKGROUND AND PURPOSE:Cells lacking the ATM (ataxia telangectasia mutated) gene are hypersensitive to DNA damage caused by a variety of insults. ATM may regulate oxidative stress-induced signaling cascades involving nuclear factor-kappaB (NF-kappaB), a transcription factor that is upstream of a wide variety of stress-responsive genes. We investigated the potential interaction of ATM and NF-kappaB after oxygen-glucose deprivation (OGD) in cerebral endothelial cells (CECs). METHODS:Primary cultures of mouse CECs were subjected to OGD in the absence or presence of ATM antisense oligonucleotides or the NF-kappaB inhibitor SN50. ATM expression was determined with the use of reverse transcription-polymerase chain reaction and Western blot, and NF-kappaB activity was assessed by electrophoretic mobility shift assay. Cells were assessed for mitochondrial DNA damage with the use of long polymerase chain reaction and were assessed for caspase-3 and caspase-8 activity with the use of fluorogenic substrates. Cell death was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and LDH release. RESULTS:OGD stimulated ATM gene expression at the mRNA and protein level in CECs as early as 1 hour after OGD initiation. ATM gene knockdown with the use of an antisense oligonucleotide suppressed OGD-induced ATM protein expression, which was accompanied by an attenuation of NF-kappaB activation and the subsequent expression of downstream genes, including the antiapoptotic gene c-IAP2. ATM knockdown also accentuated OGD-induced mitochondrial DNA damage and the activation of caspase-3 and caspase-8, leading to enhanced CEC death. The specific NF-kappaB inhibitor SN50 mimicked the effects of ATM knockdown. CONCLUSIONS:We conclude that ATM may play a cytoprotective role in OGD-induced CEC death via a NF-kappaB-dependent signaling pathway.

journal_name

Stroke

journal_title

Stroke

authors

Yin KJ,Chen SD,Lee JM,Xu J,Hsu CY

doi

10.1161/01.str.0000030316.79601.03

subject

Has Abstract

pub_date

2002-10-01 00:00:00

pages

2471-7

issue

eissn

0039-2499

issn

1524-4628

journal_volume

pub_type

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ATM gene regulates oxygen-glucose deprivation-induced nuclear factor-kappaB DNA-binding activity and downstream apoptotic cascade in mouse cerebrovascular endothelial cells.