Abstract
During chronic inflammatory response, mono- cytes/macrophages produce 92-kDa matrix metalloproteinase-9 (MMP-9), which may contribute to their extravasation, migration and tissue remodeling. Activation of peroxisome proliferator- activated factor receptor-g (PPAR-g) has been shown to inhibit MMP-9 activity. To evaluate whether ox-LDL, a PPAR-g activator, inhibits PMA-induced MMP-9 expression and activity, and if so, whether CD36 and PPAR-g are involved in this process, we investigated the effect of ox-LDL on MMP-9 expression and activity in PMA-activated human monocytic cell line U937. PMA-induced MMP-9 expression and activity were suppressed by the treatment with ox-LDL (50 mg/ml) or PPAR-g activators such as troglitazone (5 mM), ciglitazone (5 mM), and 15d- PGJ2 (1 mM) for 24 h. This ox-LDL or PPAR-g activator-mediated inhibition of MMP-9 activity was diminished by the pre-treatment of cells with a blocking antibody to CD36, or PGF2a (0.3 mM), which is a PPAR-g inhibitor, as well as overexpression of a dominant-negative form of CD36. Taken together, these results suggest that ox-LDL suppresses PMA-induced MMP-9 expression and activity through CD36-mediated activation of PPAR-g.
Highlights
The matrix metalloproteinase (MMP) enzymes have been known to play a critical role in migration of monocytes into intima during inflammatory reaction and plaque disruption of macrophages in the late stage of atherosclerosis by degrading collagen and elastin, the major components of the extracellular matrix in the basement membrane or fibrous cap
These results suggest that oxidized low-density lipoprotein (ox-LDL) may decrease matrix metalloproteinase-9 (MMP-9) expression through peroxisome proliferator-activated factor receptor-γ (PPAR-γ)-mediated suppression of nuclear factor-kappa B (NF-κB) activity
We evaluate whether exposure of phorbol 12myristate 13-acetate (PMA)-activated monocytes to ox-LDL regulates MMP-9 gene expression, and CD36 and PPAR-γ are involved in this process
Summary
The matrix metalloproteinase (MMP) enzymes have been known to play a critical role in migration of monocytes into intima during inflammatory reaction and plaque disruption of macrophages in the late stage of atherosclerosis by degrading collagen and elastin, the major components of the extracellular matrix in the basement membrane or fibrous cap. PPAR-γ activators such as thiazolidinediones (TZDs, Glitazones) inhibit monocyte cytokine and MMP-9 secretion (Jiang et al, 1998; Marx et al, 1998; Ricote et al, 1998). Ox-LDL pretreatment resulted in a significant perturbation of LPS-induced NF-κB activation (Mikita et al, 2001) These results suggest that ox-LDL may decrease MMP-9 expression through PPAR-γ-mediated suppression of NF-κB activity. Some results showed that ox-LDL induces MMP-9 gene expression in human macrophages. We evaluate whether exposure of PMA-activated monocytes to ox-LDL regulates MMP-9 gene expression, and CD36 and PPAR-γ are involved in this process. We show that the activation of CD36 with ox-LDL reduces the activity and expression of MMP-9 through PPAR-γ
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