Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction

James Haorah, Servio H. Ramirez, Kathy Schall, Daniel Smith, Rita Pandya, Yuri Persidsky

Research output: Contribution to journalArticlepeer-review

251 Scopus citations

Abstract

The blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC) regulates the passage of molecules and leukocytes in and out of the brain. Oxidative stress is a major underlying cause of neurodegenerative and neuroinflammatory disorders and BBB injury associated with them. Using human BMVEC grown on porous membranes covered with basement membrane (BM) matrix (BBB models), we demonstrated that reactive oxygen species (ROS) augmented permeability and monocyte migration across BBB. ROS activated matrix metalloproteinases (MMP-1, -2, and -9) and decreased tissue inhibitors of MMPs (TIMP-1 and -2) in a protein tyrosine kinase (PTK)-dependent manner. Increase in MMPs and PTK activities paralleled degradation of BM protein and enhanced tyrosine phosphorylation of tight junction (TJ) protein. These effects and enhanced permeability/monocyte migration were prevented by inhibitors of MMPs, PTKs, or antioxidant suggesting that oxidative stress caused BBB injury via degradation of BM protein by activated MMPs and by PTK-mediated TJ protein phosphorylation. These findings point to new therapeutic interventions ameliorating BBB dysfunction in neurological disorders such as stroke or neuroinflammation.

Original languageEnglish (US)
Pages (from-to)566-576
Number of pages11
JournalJournal of Neurochemistry
Volume101
Issue number2
DOIs
StatePublished - Apr 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Keywords

  • Blood-brain barrier
  • Brain endothelial cell
  • Matrix metalloproteinases
  • Oxidative stress
  • Protein tyrosine kinase
  • Protein tyrosine phosphatase

Fingerprint

Dive into the research topics of 'Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction'. Together they form a unique fingerprint.

Cite this