title: PPARα and PPARγ protect against HIV-1-induced MMP-9 overexpression via caveolae-associated ERK and Akt signaling.
abstract: Activation of matrix metalloproteinase-9 (MMP-9) is involved in HIV-1-induced disruption of the blood-brain barrier (BBB). In the present study, we hypothesize that peroxisome proliferator-activated receptor (PPAR)-α or PPARγ can protect against HIV-1-induced MMP-9 overexpression in brain endothelial cells (hCMEC cell line) by attenuating cellular oxidative stress and down-regulation of caveolae-associated redox signaling. Exposure to HIV-1-infected monocytes induced phosphorylation of ERK1/2 and Akt in hCMEC by 2.5- and 3.6-fold, respectively; however, these effects were attenuated by overexpression of PPARα or PPARγ and by silencing of caveolin-1 (cav-1). Coculture of hCMEC with HIV-1-infected monocytes significantly induced MMP-9 promoter and enzyme activity by 3- to 3.5-fold. Promoter mutation studies indicated that SP-1 (g1940t_g1941t) is an essential transcription factor involved in induction of MMP-9 promoter by HIV-1. In addition, HIV-1-stimulated activity of MMP-9 promoter was inhibited by mutation of AP-1 site 2 (c1918t_a1919g) and both (but not individual) NF-κB binding sites (g1389c and g1664c). PPAR overexpression, ERK1/2 or Akt inhibition, and silencing of cav-1 all effectively protected against HIV-1-induced MMP-9 promoter activity, indicating a close relationship among HIV-1-induced cerebrovascular toxicity, redox-regulated mechanisms, and functional caveolae. Such a link was further confirmed in MMP-9-deficient mice exposed to PPARα or PPARγ agonist and injected with the HIV-1-specific protein Tat into cerebral vasculature. Overall, our results indicate that ERK1/2, Akt, and cav-1 are involved in the regulatory mechanisms of PPAR-mediated protection against HIV-1-induced MMP-9 expression in brain endothelial cells.
authors.affiliation: Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Huang
authors.forename: Ibolya E
authors.initials: IE
authors.lastname: András
authors.forename: Geun Bae
authors.initials: GB
authors.lastname: Rha
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D047493:PPAR alpha / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020298:U937 Cells
chemical_list: D051242:Caveolin 1; D047493:PPAR alpha; D047495:PPAR gamma; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9