Transforming growth factor-β1 induces matrix metalloproteinase-9 expression in rat vascular smooth muscle cells via ROS-dependent ERK–NF-κB pathways

Abstract

Both matrix metalloproteinase-9 (MMP9) and transforming growth factors-β1 (TGF-β1) are the important factors in the pathogenesis of the aortic aneurysm (AA) and aortic dissection (AD). Recent studies have shown that inhibition of reactive oxygen species (ROS) production, extracellular signal-regulated kinase 1/2(ERK1/2) or NF-κB pathways is able to suppress aneurysm formation. The median layers of arterial walls are mainly the vascular smooth muscle cells (VSMCs), while the pathogenesis of AA and AD is closely related to the changes in the median layer structure. Thus, we investigated the molecular mechanisms underlying TGF-β1-induced MMP-9 expression in VSMC, the involvement of intracellular ROS and signaling molecules, including ERK1/2 and NF-κB. Rat vascular smooth muscle cells (A7r5) were used. MMP-9 expression was analyzed by gelatin zymography, western blot and RT-PCR. The involvement of intracellular ROS and signaling molecules including ERK1/2 and NF-κB in the responses was investigated using reactive oxygen scavenger N-acetylcysteine (NAC) and pharmacological inhibitors (U0126 and BAY11-7082), determined by ROS testing and western blot testing for their corresponding proteins. TGF-β1 induces MMP-9 expression via ROS-dependent signaling pathway. ROS production leads to activation of ERK1/2 and then activation of the NF-κB transcription factor. Activated NF-κB turns on transcription of the MMP-9 gene. The process in which TGF-β1 induces MMP9 expression involves the ROS-dependent ERK-NF-κB signal pathways in VSMC. This discovery raises a new regulation pathway in the VSMC, and it shows the potential to help to find a new solution to treating aortic aneurysm and aortic dissection.

p38 MAP kinase mediates transforming-growth factor-β1-induced upregulation of matrix metalloproteinase-9 but not -2 in human brain pericytes

“…Because the promoter region of the MMP-9 gene contains AP-1 sites (Clark et al, 2008), ERK and JNK are implied to also be critical for signal transduction cascades in MMP-9 upregulation. In fact, previous studies show that ERK and JNK mediate TGF-β1-induced MMP activation in astrocytes, meningeal cells, smooth muscle cells (Hsieh et al, 2010; Okamoto et al, 2009; Zhang et al, 2013). In addition, ERK and JNK may contribute to MMP-2 regulation as well (Cui et al, 2014; Kuo et al, 2006; Milkiewicz et al, 2007).…”

“…Since it has been shown previously that p38 mitogen-activated protein (MAP) kinase signaling contribute to cytokine-induced MMP-9 upregulation in astrocytes (Arai et al, 2003; Wu et al, 2004), we tested if the p38 MAP kinase signaling also mediates MMP-2 and MMP-9 upregulation in brain pericytes. In this study, upregulation of MMP-2 and MMP-9 was induced with transforming-growth factor-β1 (TGF-β1), as TGF-β1 regulates MMP-2 and MMP-9 expression in several types of cells such as astrocytes, meningeal cells, and smooth muscle cells (Hsieh et al, 2010; Okamoto et al, 2009; Zhang et al, 2013). Then p38 MAP kinase phosphorylation and pericyte secretion of MMP-2 and MMP-9 were measured to determine whether p38 MAP kinase plays a critical role in the secretion of these metalloproteinases from pericytes.…”

The Influence of Simvastatin on NGAL, Matrix Metalloproteinases and Their Tissue Inhibitors in Human Intraluminal Thrombus and Abdominal Aortic Aneurysm Tissue

“…4,5 It was documented that activation of ERK and NF-kB signalling pathways is associated with increased activity of MMP2 and MMP9 in vascular smooth muscle cells and in aneurysmal tissue during AAA progression. 26,27 The increased activity of pro-inflammatory signalling pathways and protease activity in aneurysmal wall may, in turn, influence thrombus formation. Another protein that influences the activity of MMPs is NGAL.…”

Anti-Inflammatory Effects of Adult Stem Cells in Sustained Lung Injury: A Comparative Study

“…BM-MSC, AM-MSC and hAEC reduced IL-6 protein while AM-MSC also reduced TNF-α. As both of these cytokines act synergistically to increase inflammation and fibrosis [29], the inhibition of IL-6 and TNF-α protein would be expected to significantly attenuate inflammation in AM-MSC treated mice. Interestingly, there was no increase in IL-1 between bleomycin treated mice and controls.…”

“…Possible mechanisms include an AM-MSC-induced reduction in TGF-β which would reduce collagen deposition, and the significant increase in MMP-9 activity that would increase collagen breakdown [28]. TGF-β and pro-inflammatory cytokines can induce MMP-9 [29], [30]. However, given that TNFα, IL-6, IL-1 and TGF-β protein levels were reduced with AM-MSC treatment, other factors such as BMP-7 that can down-regulate TGF-β in the lung and induce MMP may play a role [31].…”