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Deficiency of telomerase activity aggravates the blood–brain barrier disruption and neuroinflammatory responses in a model of experimental stroke
Author(s) -
Zhang Bei,
Chen Lei,
Swartz Karin R.,
Bruemmer Dennis,
Eum Sung Yong,
Huang Wen,
Seelbach Melissa,
Choi Yean Jung,
Hennig Bernhard,
Toborek Michal
Publication year - 2010
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22450
Subject(s) - telomerase , telomere , oxidative stress , blood–brain barrier , stroke (engine) , medicine , inflammation , endocrinology , pathology , biology , immunology , central nervous system , gene , genetics , mechanical engineering , engineering
Abstract Epidemiology and genetic studies indicate that patients with telomere length shorter than average are at higher risk of dying from heart disease or stroke. Telomeres are located at the ends of eukaryotic chromosomes, which demonstrate progressive length reduction in most somatic cells during aging. The enzyme telomerase can compensate for telomere loss during cell replication. The present study sought to investigate the contribution of telomerase to stroke and blood–brain barrier (BBB) dysfunction. Telomerase reverse transcriptase knockout (TERT −/− ) mice and littermate controls with normal TERT expression were subjected to a 24‐hr permanent middle cerebral artery occlusion (pMCAO). The stroke outcomes were assessed in terms of neurological scores and infarct volumes. In addition, we evaluated oxidative stress, permeability across the BBB, and integrity of tight junctions in brain microvessels. Neurological testing revealed that TERT −/− mice showed enhanced deficits compared with controls. These changes were associated with a greater infarct volume. The expression of tight junction protein ZO‐1 decreased markedly in ischemic hemispheres of TERT −/− mice. The brain microvessels of TERT −/− mice also were more susceptible to oxidative stress, revealing higher superoxide and lower glutathione levels compared with mice with normal TERT expression. Importantly, TERT deficiency potentiated the production of inflammatory mediators, such as tumor necrosis factor‐α, interleukin‐1β, and intercellular adhesion molecule‐1, in the ischemic hemispheres of mice with pMCAO. Our study suggests that TERT deficiency can predispose to the development of stroke in an experimental model of this disease. © 2010 Wiley‐Liss, Inc.