Back to Search
Start Over
Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders
- Source :
- Proceedings of the National Academy of Sciences. 109
- Publication Year :
- 2012
- Publisher :
- Proceedings of the National Academy of Sciences, 2012.
-
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.
- Subjects :
- medicine.medical_specialty
Aortic Valve Insufficiency
Notch signaling pathway
Mice, Obese
Adipose tissue
Mice, Transgenic
Inflammation
Biology
Proinflammatory cytokine
Pathogenesis
Mice
Insulin resistance
3T3-L1 Cells
Internal medicine
Adipocytes
medicine
Animals
Humans
Saphenous Vein
Chemokine CCL2
Adaptor Proteins, Signal Transducing
Metabolic Syndrome
Multidisciplinary
Receptors, Notch
Macrophages
Monocyte
Calcium-Binding Proteins
Intracellular Signaling Peptides and Proteins
Endothelial Cells
Membrane Proteins
Atherosclerosis
medicine.disease
Antibodies, Neutralizing
Immunity, Innate
Endocrinology
medicine.anatomical_structure
PNAS Plus
Adipose Tissue
Receptors, LDL
cardiovascular system
Intercellular Signaling Peptides and Proteins
Insulin Resistance
Signal transduction
medicine.symptom
Signal Transduction
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....7400c22577317b121384583a921ad903