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National Institute of Environmental Health Sciences

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Publication Detail

Title: HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells.

Authors: Hayashi, Kentaro; Pu, Hong; Tian, Jing; Andras, Ibolya E; Lee, Yong Woo; Hennig, Bernhard; Toborek, Michal

Published In J Neurochem, (2005 Jun)

Abstract: Among the different factors which can contribute to CNS alterations associated with HIV infection, Tat protein is considered to play a critical role. Evidence indicates that Tat can contribute to brain vascular pathology through induction of endothelial cell activation. In the present study, we hypothesized that Tat can affect expression of P-glycoprotein (P-gp) in brain microvascular endothelial cells (BMEC). P-gp is an ATP-dependent cellular efflux transporter which is involved in the removal of specific non-polar molecules, including drugs used for highly active antiretroviral therapy (HAART). Treatment of BMEC with Tat(1-72) resulted in P-gp overexpression both at mRNA and protein levels. These alterations were confirmed in vivo in brain vessels of mice injected with Tat(1-72) into the hippocampus. Furthermore, pre-treatment of BMEC with SN50, a specific NF-kappaB inhibitor, protected against Tat(1-72)-stimulated expression of mdr1a gene, i.e. the gene which encodes for P-gp in rodents. Tat(1-72)-mediated changes in P-gp expression were correlated with increased rhodamine 123 efflux, indicating the up-regulation of transporter functions of P-gp. These results suggest that Tat-induced overexpression of P-gp in brain microvessels may have significant implications for the development of resistance to HAART and may be a contributing factor for low efficacy of HAART in the CNS.

PubMed ID: 15934943 Exiting the NIEHS site

MeSH Terms: ATP Binding Cassette Transporter, Sub-Family B/genetics; ATP-Binding Cassette Transporters/genetics; ATP-Binding Cassette, Sub-Family B, Member 1/metabolism*; Animals; Astrocytes/metabolism; Brain/blood supply*; Brain/cytology; Cells, Cultured; Endothelial Cells/metabolism*; Gene Products, tat/pharmacology*; Male; Mice; Mice, Inbred C57BL; Microcirculation; NF-kappa B/physiology; RNA, Messenger/metabolism; Up-Regulation; tat Gene Products, Human Immunodeficiency Virus

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