PPARα and PPARγ protect against HIV-1-induced MMP-9 overexpression via caveolae-associated ERK and Akt signaling

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)-alpha or PPAR gamma 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 PPAR alpha or PPAR gamma 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-kappa B 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 PPAR alpha or PPAR gamma 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.-Huang, W., Andras, I. E., Rha, G. B., Hennig, B., Toborek, M. PPAR alpha and PPAR gamma protect against HIV-1-induced MMP-9 overexpression via caveolae-associated ERK and Akt signaling. FASEB J. 25, 3979-3988 (2011). www.fasebj.org