ERK1/2 mediates TNF‐α‐induced matrix metalloproteinase‐9 expression in human vascular smooth muscle cells via the regulation of NF‐κB and AP‐1: Involvement of the ras dependent pathway

Abstract

The expression of matrix metalloproteinase-9 (MMP-9) has been implicated in progression of atherosclerotic lesions. The role and importance of the signaling pathway in the transcriptional regulation of MMP-9 in human aortic smooth muscle cells (HASMC) was examined. Tumor necrosis factor-alpha (TNF-alpha) stimulated the secretion of MMP-9 in HASMC, as shown by zymography and immunoblot analysis. At the transcriptional levels, TNF-alpha also stimulated the 5'-flanking 710-bp promoter activity of MMP-9. Transcription factors NF-kappaB binding site (-601) and AP-1 binding site (-82) were identified as the cis-elements for TNF-alpha activation, as determined by gel shift assay and mutation analysis. Treatment with U0126, an inhibitor of the extracellular signal-regulated kinase (ERK), significantly downregulated TNF-alpha-induced MMP-9 expression and promoter activity, whereas the inactive analog U0124 had no effect. Furthermore, the transactivation of TNF-alpha-stimulated NF-kappaB and AP-1 was inhibited by U0126 treatment. Finally, the transient transfection of HASMC with dominant negative Ras (RasN17) suppressed TNF-alpha-induced ERK activity, MMP-9 production, and promoter activity. Overexpression of RasN17 also abolished the TNF-alpha-stimulated NF-kappaB and AP-1 activity. In conclusion, the findings herein indicate the activation of the Ras/ERK pathway contributes to the induction of MMP-9 expression in HASMC. In addition, the transcription factors NF-kappaB and AP-1 that are involved in the Ras/ERK-mediated control of MMP-9 regulation on HASMC in response to TNF-alpha have now been identified.

Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway

“…To date, three transcription factors (p53, NF-kB and the SP1-related retinoblastoma control proteins) appear to be responsive to the physiological radiation dose, the dose wherein cells survive or recover (Moon et al, 2004). In this study, NF-kB but not AP-1, modulated the radiation-induced MMP-9 activity in HepG2 cells on zymography.…”

Increased Expression of Matrix Metalloproteinase-1 in Systemic Vessels of Preeclamptic Women

“…26,48 Evidence presented in this study suggests that the potential mechanism for MMP-1 induction and activation may involve the generation of ROS and TNF-␣ by infiltrated neutrophils. This notion is supported by studies 13,15,16,49 showing that TNF-␣ and ROS modulate the expression of different MMPs in VSMCs and promote the activation of MMPs secreted by VSMCs. The fact that the exposure of VSMC to neutrophils or neutrophil products, such as TNF-␣ and ROS, resulted in a similar extracellular matrix gene expression pattern as that observed in blood vessels from preeclamptic women provides further evidence for the in vivo role of neutrophils in the vascular remodeling process occurring during preeclampsia.…”

“…9,10 Neutrophils produce inflammatory mediators, such as reactive oxygen species (ROS) and tumor necrosis factor (TNF) ␣, 11,12 which induce vascular expression of extracellular matrix proteins, particularly matrix metalloproteinases (MMPs). [13][14][15][16] Beyond their matrix remodeling properties, MMPs are involved in short-term biological processes, including regulation of vascular reactivity and leukocyte activation. [17][18][19][20][21] Interestingly, these biological processes are altered in women with preeclampsia.…”

Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats

“…22 Stimulation of rat cardiac fibroblasts with Ang II induces the production of both NF-kB and AP-1 transcription factors and is associated with an increase in collagen I production as well as a decrease in MMP-1 expression. 23 Previous studies [24][25][26] have reported that TNF-a-induced MMP-9 expression is regulated by activation of the transcription factors NF-kB and AP-1. In our study, we found that chronic hypertension induced overexpression of AP-1 and NF-kB.…”