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 is aimed to investigate the contribution of telomerase to stroke and the blood-brain barrier (BBB) dysfunction. Telomerase reverse transcriptase knock-out (TERT−/−) mice and littermate controls with normal TERT expression were subjected to a 24 h 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 the integrity of tight junctions in brain microvessels. Neurological testing revealed that TERT−/− mice showed enhanced deficits as compared to 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 as compared to mice with normal TERT expression. Importantly, TERT deficiency potentiated the production of inflammatory mediators, such as TNF-alpha, IL-1beta and ICAM-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.
