Received for publication September 20, 2007.
Revised February 13, 2008.
Accepted for publication February 14, 2008.

SIMVASTATIN PROTECTS AGAINST AMYLOID BETA AND HIV-1 TAT-INDUCED PROMOTER ACTIVITIES OF INFLAMMATORY GENES IN BRAIN ENDOTHELIAL CELLS

Abstract

Increased deposition of amyloid beta (A) is characteristic for normal aging and HIV-1-associated alterations of the central nervous system. In addition, both A and HIV-1 are known to induce cellular oxidative stress and disruption of the blood-brain barrier (BBB). Therefore, we hypothesize that A 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) co-cultured with a human astrocyte cell line producing Tat (SVGA-Tat cells) and exposed to A. Treatment of HBMEC with A(1-40) in the presence of SVGA-Tat cells resulted in a significant upregulation of E-selectin, CCL-2, and IL-6 promoter activities and protein levels as compared to the individual effects of A or Tat. In addition, A markedly amplified E-selectin promoter activity in HBMEC co-cultured with HIV-1-infected Jurkat T cells. Simvastatin, the HMG-CoA reductase inhibitor, effectively blocked proinflammatory reactions induced by A in co-cultures with SVGA-Tat cells or with HIV-1-infected Jurkat cells. The present study indicates that a combined exposure to A and Tat or HIV-1 can synergistically potentiate expression of inflammatory genes in brain endothelial cells. In addition, simvastatin may provide a beneficial influence by reducing these effects at the BBB level.

Key words: NFkappaB, Promoter analysis, Oxidative stress/antioxidants, Oxidative stress