HIV-Tat protein induces P-glycoprotein expression in brain microvascular endothelial cells.
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.
Hayashi
Kentaro
K
Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Pu
Hong
H
Tian
Jing
J
Andras
Ibolya E
IE
Lee
Yong Woo
YW
Hennig
Bernhard
B
Toborek
Michal
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000166:cytology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D015696:Gene Products, tat / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D015696:Gene Products, tat; D016328:NF-kappa B; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; C095122:multidrug resistance protein 3