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Rho signaling is involved in HIV‐1‐mediated upregulation of P‐glycoprotein expression in human brain endothelial cells
Author(s) -
Zhong Yu,
Hennig Bernhard,
Toborek Michal
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.882.1
Subject(s) - rhoa , downregulation and upregulation , p glycoprotein , atp binding cassette transporter , phosphorylation , microbiology and biotechnology , human brain , efflux , blood–brain barrier , signal transduction , chemistry , multiple drug resistance , biology , drug resistance , transporter , biochemistry , central nervous system , endocrinology , neuroscience , gene
Limited drug penetration into the brain is an obstacle in treatment of human immunodeficiency virus type‐1 (HIV)‐associated CNS diseases. Specific drugs used in HAART, particularly HIV‐1 protease inhibitors, are substrates for the efflux transport systems, such as P‐glycoprotein (P‐gp). P‐gp is a 170 kDa ATP‐dependent integral membrane protein and belongs to the family of ATP‐binding cassette (ABC) drug efflux transporters. We hypothesize that overexpression of P‐gp at the blood‐brain barrier level may contribute to enhanced removal of antiretroviral drugs from the brain and lead to the development of resistance to HAART. Treatment with HIV Tat protein markedly elevated GTP‐RhoA levels in human brain endothelial cells as assessed by the pull‐down assay, while the total level of RhoA was not changed. Moreover, Tat increased phosphorylation of Rho associated kinase (ROCK). Inhibition of the Rho signaling cascade by C3 exoenzyme or by Y27632 blocked Tat‐induced P‐gp overexpression. The present data indicate the critical role of the Rho signaling in upregulation of P‐gp in the brain in the context of HIV‐associated CNS diseases. It appears that the Rho cascade may be a potential target to prevent the development of HAART resistance in HIV‐infected patients. Supported by the NIH grants: MH 63022, MH 072567, NS 39254, and P42 ES 07380.