Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction.
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.
Haorah
James
J
Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5215, USA. Jhaorah@unmc.edu
Ramirez
Servio H
SH
Schall
Kathy
K
Smith
Daniel
D
Pandya
Rita
R
Persidsky
Yuri
Y
D001485:Basement Membrane / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000503:physiopathology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000201:enzymology* / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000201:enzymology / Q000503:physiopathology; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology; D019108:Tight Junctions / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D019715:Tissue Inhibitor of Metalloproteinase-1; D011505:Protein-Tyrosine Kinases; D020782:Matrix Metalloproteinases