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Article type: Research Article
Authors: Luo, Jinhua | Grammas, Paula; *
Affiliations: Garrison Institute on Aging and Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
Correspondence: [*] Correspondence to: Paula Grammas, Ph.D., Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street Stop 9424, Lubbock, Texas 79430, USA. Tel.: +1 806 743 3612; Fax: +1 806 743 3636; E-mail: [email protected].
Abstract: The vasoactive protein endothelin-1 (ET-1) is produced by vascular endothelial cells and participates in the regulation of vascular inflammation. We have previously documented that the cerebral microvasculature is a source of inflammatory proteins and a likely contributor to the pathogenesis of Alzheimer's disease (AD). In this study, we (a) compare expression of ET-1 in brain microvessels isolated from AD and control brains; (b) determine thrombin regulation of ET-1 synthesis and release in brain endothelial cells; and (c) assess the effects of ET-1 on neuronal viability in vitro. Western blot analysis indicates a significantly higher level of ET-1 in AD vessels compared to vessels from age-matched controls. ET-1 expression and secretion are both induced by the inflammatory and neurotoxic protein thrombin. Pretreatment of neuronal cultures with ET-1 significantly increases neuronal survival when cells are challenged with oxidative stress (H2O2) or thrombin. The protective effect of ET-1 is blocked by incubation with an inhibitor of the c-Jun kinase (JNK) cascade. These data demonstrate that in the brain microvasculature dysfunctional or stressed endothelial cells express ET-1 and that this protein promotes the survival of brain neurons exposed to injury.
Keywords: Endothelin-1, microvessels, neuroprotective, thrombin
DOI: 10.3233/JAD-2010-091486
Journal: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 887-896, 2010
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