Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway

Yu Gan, Xunming Ji, Xiaoming Hu, Yumin Luo, Lili Zhang, Peiying Li, Xiangrong Liu, Feng Yan, Peter Vosler, Yanqin Gao, R. Anne Stetler, Jun Chen

Research output: Contribution to journalArticle

Abstract

Aims: Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury. Results: Transgenic mice overexpressing PRX2 showed reduced brain injury and improved neurological recovery up to 3 weeks after transient focal cerebral ischemia compared to wild-type littermates. In primary cultures of cortical neurons, transfection of PRX2 but not the loss-of-catalytic-site PRX2 mutant conferred neuroprotection against cell death induced by oxygen glucose deprivation. PRX2 exhibited potent pro-survival effects in ischemic neurons by maintaining thioredoxin (Trx) in its reduced state, thereby preventing oxidative stress-mediated activation of apoptosis signal-regulating kinase 1 (ASK1) and the downstream MKK/JNK pro-death signaling pathway. PRX2 failed to provide additional neuroprotection against ischemic injury in Trx-or ASK1-knockdown neuron cultures and in mice treated with a JNK inhibitor. Innovation: This study provides evidence that neuronal overexpression of PRX2 confers prolonged neuroprotection against ischemic/reperfusion brain injury. Moreover, the results suggest a signaling pathway by which PRX2 suppresses ischemia-induced neuronal apoptosis. Conclusions: Enhanced neuronal expression and activity of PRX2 protect against ischemic neuronal injury by directly modulating the redox-sensitive Trx-ASK1 signaling complex. Antioxid. Redox Signal.

Original languageEnglish (US)
Pages (from-to)719-732
Number of pages14
JournalAntioxidants and Redox Signaling
Volume17
Issue number5
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

Fingerprint

MAP Kinase Kinase Kinase 5
Peroxiredoxins
Thioredoxins
Oxidation-Reduction
Neurons
Brain Injuries
Wounds and Injuries
Brain
Transient Ischemic Attack
Peroxides
Neuroprotective Agents
Neurodegenerative diseases
Reperfusion Injury
Neurodegenerative Diseases
Transgenic Mice
Oxidative stress
Transfection
Catalytic Domain
Scavenging
Oxidative Stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway. / Gan, Yu; Ji, Xunming; Hu, Xiaoming; Luo, Yumin; Zhang, Lili; Li, Peiying; Liu, Xiangrong; Yan, Feng; Vosler, Peter; Gao, Yanqin; Stetler, R. Anne; Chen, Jun.

In: Antioxidants and Redox Signaling, Vol. 17, No. 5, 01.09.2012, p. 719-732.

Research output: Contribution to journalArticle

Gan, Yu ; Ji, Xunming ; Hu, Xiaoming ; Luo, Yumin ; Zhang, Lili ; Li, Peiying ; Liu, Xiangrong ; Yan, Feng ; Vosler, Peter ; Gao, Yanqin ; Stetler, R. Anne ; Chen, Jun. / Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway. In: Antioxidants and Redox Signaling. 2012 ; Vol. 17, No. 5. pp. 719-732.
@article{55f8a19f6594479da00bd3d2c6cdcffc,
title = "Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway",
abstract = "Aims: Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury. Results: Transgenic mice overexpressing PRX2 showed reduced brain injury and improved neurological recovery up to 3 weeks after transient focal cerebral ischemia compared to wild-type littermates. In primary cultures of cortical neurons, transfection of PRX2 but not the loss-of-catalytic-site PRX2 mutant conferred neuroprotection against cell death induced by oxygen glucose deprivation. PRX2 exhibited potent pro-survival effects in ischemic neurons by maintaining thioredoxin (Trx) in its reduced state, thereby preventing oxidative stress-mediated activation of apoptosis signal-regulating kinase 1 (ASK1) and the downstream MKK/JNK pro-death signaling pathway. PRX2 failed to provide additional neuroprotection against ischemic injury in Trx-or ASK1-knockdown neuron cultures and in mice treated with a JNK inhibitor. Innovation: This study provides evidence that neuronal overexpression of PRX2 confers prolonged neuroprotection against ischemic/reperfusion brain injury. Moreover, the results suggest a signaling pathway by which PRX2 suppresses ischemia-induced neuronal apoptosis. Conclusions: Enhanced neuronal expression and activity of PRX2 protect against ischemic neuronal injury by directly modulating the redox-sensitive Trx-ASK1 signaling complex. Antioxid. Redox Signal.",
author = "Yu Gan and Xunming Ji and Xiaoming Hu and Yumin Luo and Lili Zhang and Peiying Li and Xiangrong Liu and Feng Yan and Peter Vosler and Yanqin Gao and Stetler, {R. Anne} and Jun Chen",
year = "2012",
month = "9",
day = "1",
doi = "10.1089/ars.2011.4298",
language = "English (US)",
volume = "17",
pages = "719--732",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "5",

}

TY - JOUR

T1 - Transgenic overexpression of peroxiredoxin-2 attenuates ischemic neuronal injury via suppression of a redox-sensitive pro-death signaling pathway

AU - Gan, Yu

AU - Ji, Xunming

AU - Hu, Xiaoming

AU - Luo, Yumin

AU - Zhang, Lili

AU - Li, Peiying

AU - Liu, Xiangrong

AU - Yan, Feng

AU - Vosler, Peter

AU - Gao, Yanqin

AU - Stetler, R. Anne

AU - Chen, Jun

PY - 2012/9/1

Y1 - 2012/9/1

N2 - Aims: Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury. Results: Transgenic mice overexpressing PRX2 showed reduced brain injury and improved neurological recovery up to 3 weeks after transient focal cerebral ischemia compared to wild-type littermates. In primary cultures of cortical neurons, transfection of PRX2 but not the loss-of-catalytic-site PRX2 mutant conferred neuroprotection against cell death induced by oxygen glucose deprivation. PRX2 exhibited potent pro-survival effects in ischemic neurons by maintaining thioredoxin (Trx) in its reduced state, thereby preventing oxidative stress-mediated activation of apoptosis signal-regulating kinase 1 (ASK1) and the downstream MKK/JNK pro-death signaling pathway. PRX2 failed to provide additional neuroprotection against ischemic injury in Trx-or ASK1-knockdown neuron cultures and in mice treated with a JNK inhibitor. Innovation: This study provides evidence that neuronal overexpression of PRX2 confers prolonged neuroprotection against ischemic/reperfusion brain injury. Moreover, the results suggest a signaling pathway by which PRX2 suppresses ischemia-induced neuronal apoptosis. Conclusions: Enhanced neuronal expression and activity of PRX2 protect against ischemic neuronal injury by directly modulating the redox-sensitive Trx-ASK1 signaling complex. Antioxid. Redox Signal.

AB - Aims: Peroxiredoxins (PRXs) are a newly characterized family of peroxide scavenging enzymes that not only help maintain cellular redox homeostasis but also may directly engage in a variety of intracellular signaling pathways. PRX2 is a neuronal-specific PRX believed to participate in cerebral antioxidant responses in several neurodegenerative diseases. This study investigates the potential neuroprotective effect and the underlying mechanism of PRX2 in models of ischemic neuronal injury. Results: Transgenic mice overexpressing PRX2 showed reduced brain injury and improved neurological recovery up to 3 weeks after transient focal cerebral ischemia compared to wild-type littermates. In primary cultures of cortical neurons, transfection of PRX2 but not the loss-of-catalytic-site PRX2 mutant conferred neuroprotection against cell death induced by oxygen glucose deprivation. PRX2 exhibited potent pro-survival effects in ischemic neurons by maintaining thioredoxin (Trx) in its reduced state, thereby preventing oxidative stress-mediated activation of apoptosis signal-regulating kinase 1 (ASK1) and the downstream MKK/JNK pro-death signaling pathway. PRX2 failed to provide additional neuroprotection against ischemic injury in Trx-or ASK1-knockdown neuron cultures and in mice treated with a JNK inhibitor. Innovation: This study provides evidence that neuronal overexpression of PRX2 confers prolonged neuroprotection against ischemic/reperfusion brain injury. Moreover, the results suggest a signaling pathway by which PRX2 suppresses ischemia-induced neuronal apoptosis. Conclusions: Enhanced neuronal expression and activity of PRX2 protect against ischemic neuronal injury by directly modulating the redox-sensitive Trx-ASK1 signaling complex. Antioxid. Redox Signal.

UR - http://www.scopus.com/inward/record.url?scp=84863447234&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863447234&partnerID=8YFLogxK

U2 - 10.1089/ars.2011.4298

DO - 10.1089/ars.2011.4298

M3 - Article

C2 - 22356734

AN - SCOPUS:84863447234

VL - 17

SP - 719

EP - 732

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 5

ER -