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.

Acetylcholine Inhibits LPS-Induced MMP-9 Production and Cell Migration via the a7 nAChR-JAK2/STAT3 Pathway in RAW264.7 Cells

“…MMP-9 gene expression is primarily regulated at the transcriptional level via transcription factors such as NF-κB and STAT3 [7,10]. Mutation of NF-κB binding sites decreased the activity of MMP-9 promoter in endothelial cells and A549 cells [26,27]. In our study, LPS enhanced the phosphorylation of NF-κB.…”

The Pro12Ala Polymorphism in the Peroxisome Proliferator-Activated Receptor Gamma-2 Gene (PPARγ2) Is Associated with Increased Risk of Coronary Artery Disease: A Meta-Analysis

“…PPARγ2 activation reduces the production of macrophage and lymphocyte cytokine, inhibits the growth, proliferation [62], [63], and migration of vascular smooth muscle cell as well as restrains the expression of endothelial cell adhesion molecule, chemokine, and matrix metalloproteinase [64]. All of these evidences suggested that PPARγ2 is benefit to prevent the initiation of atherosclerosis [65].…”

Lipopolysaccharide potentiates polychlorinated biphenyl-induced disruption of the blood–brain barrier via TLR4/IRF-3 signaling

“…For example, IRF-3 transactivates expression of proinflammatory cytokines and chemokines, including IL-6, MIP-1α, and RANTES (Sweeney et al 2010), which are known to contribute to the disruption of BBB integrity (Terao et al 2008; Toborek et al 2003). Activated IRF-3 can also stimulate expression of matrix metalloproteinases (MMPs) (Sweeney et al 2010), which were shown to be involved in proteolytic degradation of tight junction proteins (Huang et al 2011). …”