PPARalpha and PPARgamma attenuate HIV-induced dysregulation of tight junction proteins by modulations of matrix metalloproteinase and proteasome activities.
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)alpha or PPARgamma attenuated HIV-mediated dysregulation of tight junction proteins. With the use of exogenous PPARgamma agonists and silencing of PPARalpha or PPARgamma, 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.
Huang
Wen
W
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky Medical Center, 593 Wethington Bldg., 900 S Limestone, Lexington, KY 40536, USA.
Eum
Sung Yong
SY
András
Ibolya E
IE
Hennig
Bernhard
B
Toborek
Michal
M
D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D018920:Coculture Techniques; D010450:Endopeptidases / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D020868:Gene Silencing; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D062793:Occludin; D047493:PPAR alpha / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011956:Receptors, Cell Surface; D019108:Tight Junctions / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
D015815:Cell Adhesion Molecules; C407243:F11R protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D047493:PPAR alpha; D047495:PPAR gamma; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D010450:Endopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D046988:Proteasome Endopeptidase Complex; C114177:peptidylglutamylpeptide hydrolase