Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke

Ziyan Zhang, Jingqi Yan, Saeid Taheri, Ke Jian Liu, Honglian Shi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.

Original languageEnglish (US)
Pages (from-to)8-21
Number of pages14
JournalFree Radical Biology and Medicine
Volume68
DOIs
StatePublished - Mar 1 2014
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
Acetylcysteine
Stroke
HSP90 Heat-Shock Proteins
Facilitative Glucose Transport Proteins
Middle Cerebral Artery Infarction
Neuroprotective Agents
Erythropoietin
Brain
Antioxidants
Proteins
Poisons
Transient Ischemic Attack
Brain Injuries
Reperfusion
Rodentia
Animals
Animal Models

Keywords

  • Free radicals
  • HIF-1
  • Hsp90
  • NAC
  • Neuroprotection
  • Stroke

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke. / Zhang, Ziyan; Yan, Jingqi; Taheri, Saeid; Liu, Ke Jian; Shi, Honglian.

In: Free Radical Biology and Medicine, Vol. 68, 01.03.2014, p. 8-21.

Research output: Contribution to journalArticle

Zhang, Ziyan ; Yan, Jingqi ; Taheri, Saeid ; Liu, Ke Jian ; Shi, Honglian. / Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke. In: Free Radical Biology and Medicine. 2014 ; Vol. 68. pp. 8-21.
@article{6b6e8098de904efc86ee29dd486b6d3a,
title = "Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke",
abstract = "Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.",
keywords = "Free radicals, HIF-1, Hsp90, NAC, Neuroprotection, Stroke",
author = "Ziyan Zhang and Jingqi Yan and Saeid Taheri and Liu, {Ke Jian} and Honglian Shi",
year = "2014",
month = "3",
day = "1",
doi = "10.1016/j.freeradbiomed.2013.11.007",
language = "English (US)",
volume = "68",
pages = "8--21",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke

AU - Zhang, Ziyan

AU - Yan, Jingqi

AU - Taheri, Saeid

AU - Liu, Ke Jian

AU - Shi, Honglian

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.

AB - Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC's neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC's neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant's neuroprotection in ischemic stroke.

KW - Free radicals

KW - HIF-1

KW - Hsp90

KW - NAC

KW - Neuroprotection

KW - Stroke

UR - http://www.scopus.com/inward/record.url?scp=84890958335&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890958335&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2013.11.007

DO - 10.1016/j.freeradbiomed.2013.11.007

M3 - Article

C2 - 24296245

AN - SCOPUS:84890958335

VL - 68

SP - 8

EP - 21

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

ER -