Endothelin-1 is elevated in Alzheimer's disease brain microvessels and is neuroprotective.
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.
Luo
Jinhua
J
Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Grammas
Paula
P
D000544:Alzheimer Disease / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology
D019332:Endothelin-1; D013917:Thrombin