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PPARs protect against HIV‐induced MMPs overexpression by caveolae‐associated ERK and Akt signaling
Author(s) -
Huang Wen,
András Ibolya E,
Hennig Bernhard,
Toborek Michal
Publication year - 2010
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.24.1_supplement.777.16
Subject(s) - protein kinase b , mapk/erk pathway , pi3k/akt/mtor pathway , caveolin 1 , microbiology and biotechnology , caveolae , gene silencing , chemistry , downregulation and upregulation , signal transduction , matrix metalloproteinase , cancer research , biology , biochemistry , gene
Tight junctions (TJs) are the main structural and functional elements that regulate the blood‐brain barrier (BBB) integrity. Our previous data indicated that exposure of human brain microvascular endothelial cells (HBMEC) to human immunodeficiency virus‐1 (HIV) resulted in a decreased expression of TJs. Overexpression of peroxisome proliferator‐activated receptor (PPAR)‐α and γ or exposure to PPAR agonists attenuated HIV‐1‐mediated dysregulation of TJs partly by inhibition of matrix metalloproteinase (MMP) activity. Evidence indicates that MMP expression is regulated by the Ras‐ ERK and PI3K‐ Akt signaling . In addition, MMPs are closely associated with caveolae. In the present study, we hypothesize that PPARs protect against HIV‐induced MMP overexpression by attenuating cellular oxidative stress and downregulation of redox‐regulated transcription. Exposure to HIV induced protein expression of caveolin‐1, Ras, pERK and pAkt in HBMEC; however, these effects were attenuated in PPAR overexpressing cells. Silencing of caveolin‐1 further protected against HIV‐mediated activation of Ras, pERK and pAkt. These effects were confirmed in cells pretreated with PPAR agonists fenofibrate and rosiglitazone. HIV‐induced MMP promoter activity was inhibited by the Ras‐ ERK or PI3K‐ Akt inhibitors or by silencing of caveolin‐1. The present data indicate that the Ras‐ ERK, PI3K‐ Akt signaling and caveolin‐1 are involved in the mechanisms of PPAR‐mediated protection against HIV‐induced MMP expression.