Abstract
Inflammation plays a fundamental role in the inception and development of atherosclerosis (ATH). Mechanisms of inflammation include the infiltration of monocytes into the injured area and subsequent differentiation into either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. We have previously published data suggesting bone morphogenetic protein-7 (BMP-7) enhances M2 macrophage differentiation and anti-inflammatory cytokine secretion in vitro. In this regard, we hypothesized BMP-7 would inhibit plaque formation in an animal model of ATH through monocytic plasticity mediation. ATH was generated in male and female Apo E(-/-) mice via partial left carotid artery (PLCA) ligation and mice were divided into 3 groups: Sham, PLCA, and PLCA+BMP-7 (200 ug/kg; i.v.). Our data suggest that BMP-7 inhibits plaque formation and increases arterial systolic velocity. Furthermore, we report inhibition of monocyte infiltration and a decrease in associated pro-inflammatory cytokines (MCP-1, TNF-α, and IL-6) in the PLCA+BMP-7 mice. In contrast, our data suggest a significant (p<0.05) increase in M2 macrophage populations with consequential enhanced anti-inflammatory cytokine (IL-1RA, IL-10, and Arginase 1) expression following BMP-7 treatment. We have also observed that mechanisms promoting monocyte into M2 macrophage differentiation by BMP-7 involve the upregulation and activation of the BMP-7 receptor (BMP-7RII). In conclusion, we report that BMP-7 has the potential to mediate cellular plasticity and mitigate the inflammatory immune response, which results in decreased plaque formation and improved blood velocity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics*
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Arginase / genetics
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Arginase / metabolism
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Atherosclerosis / drug therapy*
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Atherosclerosis / genetics
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Blood Flow Velocity / drug effects
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Bone Morphogenetic Protein 7 / pharmacology*
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Bone Morphogenetic Protein Receptors, Type II / genetics
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Bone Morphogenetic Protein Receptors, Type II / metabolism
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Carotid Arteries / pathology
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Carotid Arteries / surgery
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Cell Differentiation
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Chemokine CCL2 / genetics
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Chemokine CCL2 / metabolism
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Humans
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Interleukin 1 Receptor Antagonist Protein / genetics
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Interleukin 1 Receptor Antagonist Protein / metabolism
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Interleukin-10 / genetics
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Interleukin-10 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Ligation
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Macrophages / drug effects*
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice
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Mice, Knockout
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Monocytes / drug effects*
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Monocytes / metabolism
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Monocytes / pathology
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Plaque, Atherosclerotic / drug therapy*
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Plaque, Atherosclerotic / genetics
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Plaque, Atherosclerotic / metabolism
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Plaque, Atherosclerotic / pathology
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Protective Agents / pharmacology*
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Signal Transduction
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Apolipoproteins E
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Bone Morphogenetic Protein 7
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Ccl2 protein, mouse
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Chemokine CCL2
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IL10 protein, mouse
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Il1rn protein, mouse
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Interleukin 1 Receptor Antagonist Protein
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Interleukin-6
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Protective Agents
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Tumor Necrosis Factor-alpha
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Interleukin-10
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Bone Morphogenetic Protein Receptors, Type II
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Arg1 protein, mouse
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Arginase