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Published on: May 31, 2016
MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B
1Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141, USA.
Abstract:
The earliest recognizable atherosclerotic lesions are fatty streaks composed of lipid-laden macrophages (foam cells). Circulating monocytes are the precursors of these foam cells, but the molecular mechanisms that govern macrophage trafficking through the vessel wall are poorly understood. Monocyte chemoattractant protein-1 (MCP-1), a member of the chemokine (chemotactic cytokine) family, is a potent monocyte agonist that is upregulated by oxidized lipids. Recent studies in hypercholesterolemic mice lacking apo E or the low-density lipoprotein receptor have suggested a role for MCP-1 in monocyte recruitment to early atherosclerotic lesions. To determine if MCP-1 is critically involved in atherogenesis in the setting of elevated physiological plasma cholesterol levels, we deleted the MCP-1 gene in transgenic mice expressing human apo B. Here we report that the absence of MCP-1 provides dramatic protection from macrophage recruitment and atherosclerotic lesion formation in apo B transgenic mice, without altering lipoprotein metabolism. Taken together with the results of earlier studies, these data provide compelling evidence that MCP-1 plays a critical role in the initiation of atherosclerosis.
Insights
Monocyte chemoattractant protein-1 (MCP-1) drives foam cell formation in early atherosclerosis. Removing MCP-1 significantly protected against macrophage recruitment and lesion development in high cholesterol models.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Atherosclerosis begins with fatty streaks, involving lipid-laden macrophages (foam cells).
- Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that attracts monocytes and is upregulated by oxidized lipids.
- Previous studies suggest MCP-1's role in monocyte recruitment to early atherosclerotic lesions in specific mouse models.
Purpose of the Study:
- To investigate the critical role of MCP-1 in atherogenesis under elevated physiological plasma cholesterol levels.
- To determine if MCP-1 is essential for monocyte recruitment and atherosclerotic lesion formation in a relevant genetic model.
Main Methods:
- Generated transgenic mice expressing human apo B to mimic high physiological cholesterol.
- Deleted the MCP-1 gene in these apo B transgenic mice.
- Assessed macrophage recruitment and atherosclerotic lesion formation.
Main Results:
- Absence of MCP-1 conferred significant protection against macrophage recruitment to vessel walls.
- MCP-1 deficiency dramatically reduced atherosclerotic lesion formation in apo B transgenic mice.
- Lipoprotein metabolism remained unaltered in mice lacking MCP-1.
Conclusions:
- MCP-1 is critically involved in the initiation of atherosclerosis.
- Targeting MCP-1 may represent a therapeutic strategy for preventing early lesion development.
- These findings solidify MCP-1's importance in monocyte trafficking during atherogenesis.
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