Proceedings of the National Academy of Sciences - PNAS, 2012-07, Vol.109 (27), p.E1868-E1877
2012
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- Autor(en) / Beteiligte
- Titel
- Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2012-07, Vol.109 (27), p.E1868-E1877
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2012
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1116889109Titel-ID: cdi_pnas_primary_109_27_E1868
- Format
- –
- Schlagworte
- 3T3-L1 Cells, adaptive immunity, Adipocytes - cytology, Adipocytes - metabolism, Adipose Tissue - metabolism, adults, Animals, antibodies, Antibodies, Neutralizing - pharmacology, Aortic Valve Insufficiency - immunology, Aortic Valve Insufficiency - metabolism, Atherosclerosis, Atherosclerosis - immunology, Atherosclerosis - metabolism, Atherosclerosis - therapy, Biological Sciences, calcification, Cell culture, chemokine CCL2, Chemokine CCL2 - metabolism, diet, Endothelial Cells - cytology, Endothelial Cells - metabolism, Global health, Humans, Immunity, Innate - physiology, inflammation, Insulin resistance, Insulin Resistance - physiology, Intercellular Signaling Peptides and Proteins - immunology, Intercellular Signaling Peptides and Proteins - metabolism, Intracellular Signaling Peptides and Proteins - genetics, Intracellular Signaling Peptides and Proteins - immunology, Intracellular Signaling Peptides and Proteins - metabolism, macrophages, Macrophages - immunology, Macrophages - metabolism, Membrane Proteins - genetics, Membrane Proteins - immunology, Membrane Proteins - metabolism, metabolic diseases, Metabolic disorders, Metabolic Syndrome - immunology, Metabolic Syndrome - metabolism, Metabolic Syndrome - therapy, Mice, Mice, Obese, Mice, Transgenic, Molecules, neutralization, pathogenesis, phenotype, PNAS Plus, Receptors, LDL - genetics, Receptors, Notch - metabolism, Rodents, Saphenous Vein - cytology, Signal transduction, Signal Transduction - physiology, transcription factor NF-kappa B