Extracellular chromatin is an important mediator of ischemic stroke in mice

TY - JOUR

T1 - Extracellular chromatin is an important mediator of ischemic stroke in mice

AU - De Meyer, Simon F

AU - Suidan, Georgette L

AU - Fuchs, Tobias A

AU - Monestier, Marc

AU - Wagner, Denisa D

PY - 2012/8/1

Y1 - 2012/8/1

N2 - OBJECTIVE: Recently, a growing number of studies have revealed a prothrombotic and cytotoxic role for extracellular chromatin. Cerebral ischemia/reperfusion injury is characterized by a significant amount of cell death and neutrophil activation, both of which may result in the release of chromatin. The goal of this study was to assess the effect of extracellular chromatin in ischemic stroke using a mouse model of transient middle cerebral artery occlusion.METHODS AND RESULTS: Similar to reports in stroke patients, we observed increased levels of circulating nucleosomes and DNA after ischemic stroke in mice. In addition, we observed that general hypoxia also augmented extracellular chromatin. We hypothesized that targeting extracellular chromatin components would be protective in ischemic stroke. Indeed, treatment with recombinant human DNase 1 significantly improved stroke outcome. Neutralization of histones using an antihistone antibody was also protective as evidenced by smaller infarct volumes, whereas increasing levels of extracellular histones via histone infusion exacerbated stroke outcome by increasing infarct size and worsening functional outcome.CONCLUSIONS: Our results indicate that extracellular chromatin is generated and is detrimental during cerebral ischemia/reperfusion in mice. Targeting DNA and histones may be a new therapeutic strategy to limit injury resulting from ischemic stroke.

AB - OBJECTIVE: Recently, a growing number of studies have revealed a prothrombotic and cytotoxic role for extracellular chromatin. Cerebral ischemia/reperfusion injury is characterized by a significant amount of cell death and neutrophil activation, both of which may result in the release of chromatin. The goal of this study was to assess the effect of extracellular chromatin in ischemic stroke using a mouse model of transient middle cerebral artery occlusion.METHODS AND RESULTS: Similar to reports in stroke patients, we observed increased levels of circulating nucleosomes and DNA after ischemic stroke in mice. In addition, we observed that general hypoxia also augmented extracellular chromatin. We hypothesized that targeting extracellular chromatin components would be protective in ischemic stroke. Indeed, treatment with recombinant human DNase 1 significantly improved stroke outcome. Neutralization of histones using an antihistone antibody was also protective as evidenced by smaller infarct volumes, whereas increasing levels of extracellular histones via histone infusion exacerbated stroke outcome by increasing infarct size and worsening functional outcome.CONCLUSIONS: Our results indicate that extracellular chromatin is generated and is detrimental during cerebral ischemia/reperfusion in mice. Targeting DNA and histones may be a new therapeutic strategy to limit injury resulting from ischemic stroke.

KW - Animals

KW - Anoxia

KW - Brain Ischemia

KW - Chromatin

KW - Deoxyribonuclease I

KW - Histones

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Nucleosomes

KW - Stroke

U2 - 10.1161/ATVBAHA.112.250993

DO - 10.1161/ATVBAHA.112.250993

M3 - SCORING: Journal article

C2 - 22628431

VL - 32

SP - 1884

EP - 1891

JO - ARTERIOSCL THROM VAS

JF - ARTERIOSCL THROM VAS

SN - 1079-5642

IS - 8

ER -