Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo

Rong Rong Tao, Huan Wang, Ling Juan Hong, Ji Yun Huang, Ying Mei Lu, Mei Hua Liao, Wei Feng Ye, Nan Nan Lu, Dan Yan Zhu, Qian Huang, Kohji Fukunaga, Yi Jia Lou, Ikuo Shoji, Christopher Stuart Wilcox, En Yin Lai, Feng Han

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

Abstract

Aims: Although there is accumulating evidence that increased formation of reactive nitrogen species in cerebral vasculature contributes to the progression of ischemic damage, but the underlying molecular mechanisms remain elusive. Peroxiredoxin 1 (Prx1) can initiate the antioxidant response by scavenging free radicals. Therefore, we tested the hypothesis that Prx1 regulates the susceptibility to nitrosative stress damage during cerebral ischemia in vitro and in vivo. Results: Proteomic analysis in endothelial cells revealed that Prx1 was upregulated after stress-related oxygen-glucose deprivation (OGD). Although peroxynitrite upregulated Prx1 rapidly, this was followed by its polyubiquitination within 6 h after OGD mediated by the E3 ubiquitin ligase E6-associated protein (E6AP). OGD colocalized E6AP with nitrotyrosine in endothelial cells. To assess translational relevance in vivo, mice were studied after middle cerebral artery occlusion (MCAO). This was accompanied by Prx1 ubiquitination and degradation by the activation of E6AP. Furthermore, brain delivery of a lentiviral vector encoding Prx1 in mice inhibited blood-brain barrier leakage and neuronal damage significantly following MCAO. Innovation and Conclusions: Nitrosative stress during ischemic insult activates E6AP E3 ubiquitin ligase that ubiquitinates Prx1 and subsequently worsens cerebral damage. Thus, targeting the Prx1 antioxidant defense pathway may represent a novel treatment strategy for neurovascular protection in stroke. Antioxid. Redox Signal. 21, 1-16.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalAntioxidants and Redox Signaling
Volume21
Issue number1
DOIs
Publication statusPublished - 2014 Jul 1

ASJC Scopus subject areas

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

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