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Interaction between monocytes and vascular smooth muscle cells enhances matrix metalloproteinase-1 production
Abstract:
Matrix metalloproteinase-1 (MMP-1) plays an important role in atherosclerotic plaque rupture. The purpose of this study was to investigate the expression of MMP-1 by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cells) were cocultured. MMP-1 levels were measured by enzyme-linked immunosorbent assay. Collagenolytic activity was determined by fluorescent labeled-collagen digestion. Immunohistochemistry was performed to determine which types of cells produce MMP-1. Adding THP-1 cells to VSMCs markedly increased the MMP-1 levels and activity of the culture media. MMP-1 levels were maximal when the cellular ratio of THP-1 cells/VSMCs was 1.0. Immunohistochemistry revealed that both types of cells in the coculture produced MMP-1. Separated coculture experiments showed that both direct contact and a soluble factor(s) contributed to MMP-1 production. Neutralizing anti-interleukin (IL)-6 and tumor necrosis factor-alpha antibodies inhibited coculture conditioned medium-induced MMP-1 production by VSMCs and THP-1 cells. Protein kinase C inhibitors, tyrosine kinase inhibitors, and a mitogen-activated protein kinase inhibitor significantly inhibited MMP-1 production by cocultures. Direct cell-to-cell interaction between THP-1 cells and VSMCs enhanced MMP-1 synthesis in both types of cells. Increased local MMP-1 production and activity induced by monocyte-VSMC interaction play an important pathogenic role in atherosclerotic plaque rupture.
Insights
Monocyte and vascular smooth muscle cell interactions significantly increase matrix metalloproteinase-1 (MMP-1) production. This enhanced MMP-1 expression by monocytes and VSMCs contributes to atherosclerotic plaque rupture.
Area of Science:
- Cardiovascular Biology
- Cellular Interactions
- Atherosclerosis Research
Background:
- Matrix metalloproteinase-1 (MMP-1) is implicated in atherosclerotic plaque instability.
- Understanding monocyte-vascular smooth muscle cell (VSMC) interactions is crucial for elucidating plaque rupture mechanisms.
Purpose of the Study:
- To investigate MMP-1 expression driven by cell-to-cell contact between monocytes (THP-1 cells) and VSMCs.
- To identify signaling pathways involved in MMP-1 production during these interactions.
Main Methods:
- Coculture of human VSMCs and THP-1 cells.
- Enzyme-linked immunosorbent assay (ELISA) for MMP-1 quantification.
- Collagenolytic activity assays.
- Immunohistochemistry to localize MMP-1 production.
- Inhibition studies using neutralizing antibodies (anti-IL-6, anti-TNF-α) and kinase inhibitors (PKC, tyrosine kinase, MAPK).
Main Results:
- Coculture of THP-1 cells with VSMCs markedly elevated MMP-1 levels and collagenolytic activity.
- MMP-1 production was highest at a 1:1 ratio of THP-1 cells to VSMCs.
- Both cell types produced MMP-1, influenced by direct contact and soluble factors.
- Interleukin-6 and tumor necrosis factor-alpha mediated MMP-1 production.
- PKC, tyrosine kinase, and MAPK pathways were involved in regulating MMP-1 synthesis.
Conclusions:
- Direct cell-to-cell interaction between monocytes and VSMCs significantly enhances MMP-1 synthesis in both cell types.
- Increased local MMP-1 production via monocyte-VSMC interaction is a key pathogenic factor in atherosclerotic plaque rupture.