PPARα and PPARγ attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities

Wen Huang, Yong Eum Sung, Ibolya Edit Andras, Bernhard Hennig, Michal J Toborek

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

The blood-brain barrier (BBB) plays an important role in HIV trafficking into the brain and the development of the central nervous system complications in HIV infection. Tight junctions are the main structural and functional elements that regulate the BBB integrity. Exposure of human brain microvascular endothelial cells (hCMEC/D3 cell line) to HIV-infected monocytes resulted in decreased expression of tight junction proteins, such as junctional adhesion molecule-A (JAM)-A, occludin, and zonula occludens (ZO)-1. Control experiments involved exposure to uninfected monocytes. Alterations of tight junction protein expression were associated with increased endothelial permeability and elevated transendothelial migration of HIV-infected monocytes across an in vitro model of the BBB. Notably, overexpression of the peroxisome proliferator-activated receptor (PPAR)α or PPARγ attenuated HIV-mediated dysregulation of tight junction proteins. With the use of exogenous PPARγ agonists and silencing of PPARα or PPARγ, these protective effects were connected to down-regulation of matrix metalloproteinase (MMP) and proteasome activities. Indeed, the HIV-induced decrease in the expression of JAM-A and occludin was restored by inhibition of MMP activity. Moreover, both MMP and proteasome inhibitors attenuated HIV-mediated altered expression of ZO-1. The present data indicate that down-regulation of MMP and proteasome activities constitutes a novel mechanism of PPAR-induced protections against HIV-induced disruption of brain endothelial cells.

Original languageEnglish
Pages (from-to)1596-1606
Number of pages11
JournalFASEB Journal
Volume23
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

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Tight Junction Proteins
Peroxisome Proliferator-Activated Receptors
Proteasome Endopeptidase Complex
Matrix Metalloproteinases
Modulation
HIV
Junctional Adhesion Molecule A
Tight Junctions
Occludin
Blood-Brain Barrier
Brain
Endothelial cells
Monocytes
Down-Regulation
Endothelial Cells
Proteasome Inhibitors
Matrix Metalloproteinase Inhibitors
Transendothelial and Transepithelial Migration
Neurology
HIV Infections

Keywords

  • Blood-brain barrier
  • Brain endothelial cells
  • Human immunodeficiency virus-1
  • Peroxisome proliferator-activated receptor

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology
  • Medicine(all)

Cite this

PPARα and PPARγ attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities. / Huang, Wen; Sung, Yong Eum; Andras, Ibolya Edit; Hennig, Bernhard; Toborek, Michal J.

In: FASEB Journal, Vol. 23, No. 5, 01.05.2009, p. 1596-1606.

Research output: Contribution to journalArticle

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