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Possible Mechanisms of Di(2-ethylhexyl) Phthalate-Induced MMP-2 and MMP-9 Expression in A7r5 Rat Vascular Smooth
Mei-Fen Shih1, Kuang-Hung Pan2, Jong Yuh Cherng3
1Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan 717, Taiwan. meifenshih@mail.cnu.edu.tw.
Abstract:
Proliferation and migration of vascular smooth muscle cells (VSMC) are important in the development and/or progression of many cardiovascular diseases, including atherosclerosis. Evidence shows that matrix metalloproteinase (MMP)-2 and MMP-9 are related to the pathogenesis of atherosclerosis. The expressions of MMP-2 and MMP-9 in atherosclerosis are regulated via various pathways, such as p38 mitogen activated protein kinase (MAPK), extracellular signal regulated kinase 1 and 2 (ERK1/2), Akt, and nuclear factor kappa (NF-κB). Di(2-ethylhexyl) phthalate (DEHP) has been shown to induce atherosclerosis by increasing tumor necrosis factor (TNF)-α, interleukin (IL)-6, and intercellular adhesion molecule (ICAM) productions. However, whether DEHP poses any effects on MMP-2 or MMP-9 expression in VSMC has not yet been answered. In our studies, rat aorta VSMC was treated with DEHP (between 2 and 17.5 ppm) and p38 MAPK, ERK1/2, Akt, NF-κB, and MMP-2 and MMP-9 proteins and activities were measured. Results showed that the presence of DEHP can induce higher MMP-2 and MMP-9 expression than the controls. Similar results on MMP-regulating proteins, i.e., p38 MAPK, ERK1/2, Akt, and NF-κB, were also observed. In summary, our current results have showed that DEHP can be a potent inducer of atherosclerosis by increasing MMP-2 and MMP-9 expression at least through the regulations of p38 MAPK, ERK1/2, Akt, and NF-κB.
Insights
Di(2-ethylhexyl) phthalate (DEHP) exposure increases matrix metalloproteinase (MMP)-2 and MMP-9 expression in vascular smooth muscle cells. This suggests DEHP may promote atherosclerosis by affecting key signaling pathways like p38 MAPK and NF-κB.
Area of Science:
- Cardiovascular Biology
- Molecular Toxicology
- Cellular Signaling
Background:
- Vascular smooth muscle cell (VSMC) proliferation and migration are critical in cardiovascular diseases like atherosclerosis.
- Matrix metalloproteinases (MMP)-2 and MMP-9 are implicated in atherosclerotic pathogenesis.
- MMP expression is regulated by pathways including p38 MAPK, ERK1/2, Akt, and NF-κB.
Purpose of the Study:
- To investigate the effect of Di(2-ethylhexyl) phthalate (DEHP) on MMP-2 and MMP-9 expression in rat aorta VSMCs.
- To explore the underlying molecular mechanisms involving key signaling pathways.
Main Methods:
- Rat aorta VSMCs were treated with varying concentrations of DEHP.
- Expression and activity of MMP-2, MMP-9, p38 MAPK, ERK1/2, Akt, and NF-κB were measured.
Main Results:
- DEHP treatment significantly increased MMP-2 and MMP-9 expression and activity compared to controls.
- DEHP exposure also modulated the expression of p38 MAPK, ERK1/2, Akt, and NF-κB proteins.
Conclusions:
- DEHP acts as a potent inducer of atherosclerosis by upregulating MMP-2 and MMP-9 expression in VSMCs.
- These effects are mediated, at least in part, through the regulation of p38 MAPK, ERK1/2, Akt, and NF-κB signaling pathways.
