TY - JOUR
T1 - HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells
AU - Hayashi, Kentaro
AU - Pu, Hong
AU - Tian, Jing
AU - Andras, Ibolya E.
AU - Lee, Yong Woo
AU - Hennig, Bernhard
AU - Toborek, Michal
PY - 2005/6
Y1 - 2005/6
N2 - 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 Tat1-72 resulted in P-gp overexpression both at mRNA and protein levels. These alterations were confirmed in vivo in brain vessels of mice injected with Tat1-72 into the hippocampus. Furthermore, pre-treatment of BMEC with SN50, a specific NF-κB inhibitor, protected against Tat1-72-stimulated expression of mdr1a gene, i.e. the gene which encodes for P-gp in rodents. Tat1-72-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.
AB - 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 Tat1-72 resulted in P-gp overexpression both at mRNA and protein levels. These alterations were confirmed in vivo in brain vessels of mice injected with Tat1-72 into the hippocampus. Furthermore, pre-treatment of BMEC with SN50, a specific NF-κB inhibitor, protected against Tat1-72-stimulated expression of mdr1a gene, i.e. the gene which encodes for P-gp in rodents. Tat1-72-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.
KW - Blood-brain barrier
KW - Endothelial cell
KW - HIV-Tat protein
KW - Highly active antiretroviral therapy
KW - Nuclear factor kappa B
KW - P-glycoprotein
UR - http://www.scopus.com/inward/record.url?scp=20144379266&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=20144379266&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2005.03114.x
DO - 10.1111/j.1471-4159.2005.03114.x
M3 - Article
C2 - 15934943
AN - SCOPUS:20144379266
SN - 0022-3042
VL - 93
SP - 1231
EP - 1241
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -