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

Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery (I.E.A., G.B.R., W.H., S.Y.E., M.T.) and College of Agriculture (B.H.), University of Kentucky, Lexington, Kentucky; Institut COCHIN, Institut National de la Santé et de la Recherche Médicale U567, Paris, France (P.-O.C.); and Department of Life Sciences, the Open University, Milton Keynes, United Kingdom (I.A.R.)

Increased deposition of amyloid β (Aβ) is characteristic for normal aging and human immunodeficiency virus-1 (HIV-1)-associated alterations of the central nervous system. In addition, both Aβ and HIV-1 are known to induce cellular oxidative stress and disruption of the blood-brain barrier (BBB). Therefore, we hypothesize that Aβ 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 Aβ. Treatment of HBMEC with Aβ(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 Aβ or Tat. In addition, Aβ 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 Aβ in cocultures with SVGA-Tat cells or with HIV-1-infected Jurkat cells. The present study indicates that a combined exposure to Aβ 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.

Address correspondence to: Dr. Michal Toborek, Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky Medical Center, 593 Wethington Bldg., 900 S Limestone, Lexington, KY 40536. E-mail: michal.toborek{at}uky.edu