Recombinant milk fat globule-EGF Factor-8 Reduces oxidative stress via integrin β3/nuclear factor erythroid 2-related factor 2/heme oxygenase pathway in subarachnoid hemorrhage rats

Fei Liu, Qin Hu, Bo Li, Anatol Manaenko, Yujie Chen, Junjia Tang, Zongduo Guo, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Purpose - Milk fat globule-EGF factor-8 (MFGE8) has been reported to be neuroprotective in ischemic stroke. However, the effects of MFGE8 in early brain injury after subarachnoid hemorrhage (SAH) have not been investigated. We investigated the role of MFGE8 in early brain injury and the potential mechanisms in antioxidation after SAH.

Methods - Two dosages (1 μg and 3.3 μg) of recombinant human MFGE8 were injected intracerebroventricularly at 1.5 hours after SAH. SAH grades, neurological scores, and brain water content were measured at 24 and 72 hours. For mechanistic study, MFGE8 siRNA, integrin β3 siRNA, and heme oxygenase (HO) inhibitor SnPP IX were used for intervention. The oxidative stress and expression of MFGE8, integrin β3, HO-1, extracellular signal-regulated kinase, and nuclear factor erythroid 2-related factor 2 were measured by Western blots 24 hours after SAH.

Results - The expression of MFGE8 and HO-1 increased and peaked 24 hours after SAH. Administration of recombinant human MFGE8 decreased brain water content and improved neurological functions both at 24 hours and at 72 hours after SAH. Recombinant human MFGE8 reduced oxidative stress and enhanced the expression of extracellular signalregulated kinase, nuclear factor erythroid 2-related factor 2, and HO-1; and the effects were abolished by integrin β3 siRNA and HO inhibitor SnPP IX.

Conclusions - Recombinant MFGE8 attenuated oxidative stress that may be mediated by integrin β3/nuclear factor erythroid 2-related factor 2/HO pathway after SAH. Recombinant MFGE8 may serve as an alternative treatment to ameliorate early brain injury for SAH patients.

Original languageEnglish
Pages (from-to)3691-3697
Number of pages7
JournalStroke
Volume45
Issue number12
DOIs
StatePublished - Dec 11 2014

ASJC Scopus Subject Areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Keywords

  • Heme oxygenase-1
  • MFGE8 protein, rat
  • Oxidative stress
  • Subarachnoid hemorrhage
  • Heme Oxygenase (Decyclizing)/metabolism
  • Humans
  • Recombinant Proteins/pharmacology
  • Rats
  • Male
  • Rats, Sprague-Dawley
  • Signal Transduction/drug effects
  • Subarachnoid Hemorrhage/metabolism
  • Blotting, Western
  • Milk Proteins/metabolism
  • Oxidative Stress/drug effects
  • Animals
  • Fluorescent Antibody Technique
  • Integrin beta3/metabolism
  • NF-E2-Related Factor 2/metabolism
  • Neuroprotective Agents/metabolism
  • Antigens, Surface/metabolism
  • Disease Models, Animal

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