Abstract
Atherosclerosis and insulin resistance are major components of the cardiometabolic syndrome, a global health threat associated with a systemic inflammatory state. Notch signaling regulates tissue development and participates in innate and adaptive immunity in adults. The role of Notch signaling in cardiometabolic inflammation, however, remains obscure. We noted that a high-fat, high-cholesterol diet increased expression of the Notch ligand Delta-like 4 (Dll4) in atheromata and fat tissue in LDL-receptor-deficient mice. Blockade of Dll4-Notch signaling using neutralizing anti-Dll4 antibody attenuated the development of atherosclerosis, diminished plaque calcification, improved insulin resistance, and decreased fat accumulation. These changes were accompanied by decreased macrophage accumulation, diminished expression of monocyte chemoattractant protein-1 (MCP-1), and lower levels of nuclear factor-κB (NF-κB) activation. In vitro cell culture experiments revealed that Dll4-mediated Notch signaling increases MCP-1 expression via NF-κB, providing a possible mechanism for in vivo effects. Furthermore, Dll4 skewed macrophages toward a proinflammatory phenotype ("M1"). These results suggest that Dll4-Notch signaling plays a central role in the shared mechanism for the pathogenesis of cardiometabolic disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3-L1 Cells
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Adaptor Proteins, Signal Transducing
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Adipocytes / cytology
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Adipocytes / metabolism
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Adipose Tissue / metabolism
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Animals
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Antibodies, Neutralizing / pharmacology*
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Aortic Valve Insufficiency / immunology
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Aortic Valve Insufficiency / metabolism
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Atherosclerosis / immunology
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Atherosclerosis / metabolism*
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Atherosclerosis / therapy
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Calcium-Binding Proteins
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Chemokine CCL2 / metabolism
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Endothelial Cells / cytology
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Endothelial Cells / metabolism
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Humans
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Immunity, Innate / physiology
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Insulin Resistance / physiology
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Intercellular Signaling Peptides and Proteins / immunology
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Intercellular Signaling Peptides and Proteins / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology
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Intracellular Signaling Peptides and Proteins / metabolism*
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Macrophages / immunology
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Macrophages / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Metabolic Syndrome / immunology
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Metabolic Syndrome / metabolism*
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Metabolic Syndrome / therapy
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Mice
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Mice, Obese
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Mice, Transgenic
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Receptors, LDL / genetics
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Receptors, Notch / metabolism
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Saphenous Vein / cytology
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Signal Transduction / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Neutralizing
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Calcium-Binding Proteins
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Ccl2 protein, mouse
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Chemokine CCL2
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DLL4 protein, human
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DLL4 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, LDL
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Receptors, Notch