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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Weissleder, Ralph Gorgun, Cem Z. Novobrantseva, Tatiana I. Swirski, Filip K. Kotelianski, Victor Yamazaki, Hiroyuki Yagita, Hideo Aikawa, Elena Hotamisligil, Gökhan S. Croce, Kevin Aster, Jon C. Chudnovskiy, Aleksey Aikawa, Masanori Fukuda, Daiju |
| Description | Author Affiliation: Fukuda D ( Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 27 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antibodies, Neutralizing Pharmacology Atherosclerosis Metabolism Intercellular Signaling Peptides And Proteins Intracellular Signaling Peptides And Proteins Membrane Proteins Metabolic Syndrome X 3T3-L1 Cells Adipocytes Cytology Adipose Tissue Animals Aortic Valve Insufficiency Immunology Therapy Chemokine CCL2 Endothelial Cells Immunity, Innate Physiology Insulin Resistance Genetics Macrophages Mice Mice, Obese Mice, Transgenic Receptors, LDL Receptors, Notch Saphenous Vein Signal Transduction Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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