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Simvastatin Protects against Amyloid β and HIV-1 Tat-Induced Promoter Activities of Inflammatory Genes in Brain Endothelial Cells

András, I. E.; Rha, G.; Huang, W.; Eum, S.; Couraud, P. O.; Romero, I. A.; Henning, B. and Toborek, M. (2008). Simvastatin Protects against Amyloid β and HIV-1 Tat-Induced Promoter Activities of Inflammatory Genes in Brain Endothelial Cells. Molecular Pharmacology, 73(5) pp. 1424–1433.

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Increased deposition of amyloid beta (Abeta) is characteristic for normal aging and human immunodeficiency virus-1 (HIV-1)-associated alterations of the central nervous system. In addition, both Abeta and HIV-1 are known to induce cellular oxidative stress and disruption of the blood-brain barrier (BBB). Therefore, we hypothesize that Abeta and HIV-1 protein Tat can potentiate their proinflammatory effects at the brain endothelium level. To address this hypothesis, we studied promoter activity of three proinflammatory genes in an in vitro BBB model of human brain microvascular endothelial cells (HBMEC) cocultured with a human astrocyte cell line producing Tat (SVGA-Tat cells) and exposed to Abeta. Treatment of HBMEC with Abeta(1-40) in the presence of SVGA-Tat cells resulted in a significant up-regulation of E-selectin, CC chemokine ligand-2, and interleukin-6 promoter activities and protein levels compared with the individual effects of Abeta or Tat. In addition, Abeta markedly amplified E-selectin promoter activity in HBMEC cocultured with HIV-1-infected Jurkat T cells. Simvastatin, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, effectively blocked proinflammatory reactions induced by Abeta in cocultures with SVGA-Tat cells or with HIV-1-infected Jurkat cells. The present study indicates that a combined exposure to Abeta and Tat or HIV-1 can synergistically potentiate the expression of inflammatory genes in brain endothelial cells. In addition, simvastatin may provide a beneficial influence by reducing these effects at the BBB level.

Item Type: Journal Article
ISSN: 0026-895X
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 10653
Depositing User: Ignacio A Romero
Date Deposited: 30 Apr 2008
Last Modified: 14 Jan 2016 16:56
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