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PPARs attenuate HIV‐1‐induced dysregulation of tight junction protein expression in human brain endothelial cells
Author(s) -
Huang Wen,
András Ibolya E,
Eum Sung Yong,
Zhong Yu,
Couraud PierreOlivier,
Hennig Bernhard,
Toborek Michal
Publication year - 2008
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.22.1_supplement.734.11
Subject(s) - occludin , lactacystin , tight junction , blood–brain barrier , microbiology and biotechnology , proteasome , matrix metalloproteinase , proteasome inhibitor , u937 cell , in vitro , immunology , biology , chemistry , neuroscience , central nervous system , biochemistry
Blood‐brain barrier (BBB) plays an important role in HIV‐1 trafficking into the brain and the development of CNS complications in the course of HIV‐1 infection. Exposure of human brain microvascular brain endothelial cells (HBMEC) to HIV‐1‐infected monocytic U937 cells resulted in decreased expression of tight junction proteins, such as JAM‐A, ZO‐1, and ZO‐2. In addition, exposure to HIV‐1‐infected U937 cells stimulated their transendothelial migration and decreased transendothelial resistance of an in vitro model of the BBB. Most importantly, these effects were markedly attenuated by overexpression of PPARalpha or PPARgamma in HBMEC. To determine the mechanisms involved in HIV‐1‐induced disruption of tight junctions, our studies focused on the role of matrix metalloproteinases (MMPs) and proteasome. HIV‐1 induced dysregulation of JAM‐A and occludin expression was attenuated by GM6001, a general inhibitor of MMPs. In addition, alteration of ZO‐1 and ZO‐2 expression was inhibited by blocking of proteasome activity by lactacystin. Overexpression of PPARs resulted in decreased MMP and proteasome activities. The present data indicate that PPARs play important roles in protecting against HIV‐1 induced dysfunction of brain endothelial cells by attenuating MMP and proteasome activities. Supported by NS39254, MH63022, and MH072567.