RGD Reference Report - Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. - Rat Genome Database

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Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders.

Authors: Fukuda, Daiju  Aikawa, Elena  Swirski, Filip K  Novobrantseva, Tatiana I  Kotelianski, Victor  Gorgun, Cem Z  Chudnovskiy, Aleksey  Yamazaki, Hiroyuki  Croce, Kevin  Weissleder, Ralph  Aster, Jon C  Hotamisligil, Gökhan S  Yagita, Hideo  Aikawa, Masanori 
Citation: Fukuda D, etal., Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):E1868-77. doi: 10.1073/pnas.1116889109. Epub 2012 Jun 13.
RGD ID: 155641244
Pubmed: PMID:22699504   (View Abstract at PubMed)
PMCID: PMC3390871   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1116889109   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
DLL4Humanatherosclerosis amelioratesISODll4 (Mus musculus) RGD 
Dll4Ratatherosclerosis amelioratesISODll4 (Mus musculus) RGD 
Dll4Mouseatherosclerosis amelioratesIMP  RGD 
DLL4HumanCalcification of Aortic Valve amelioratesISODll4 (Mus musculus) RGD 
Dll4RatCalcification of Aortic Valve amelioratesISODll4 (Mus musculus) RGD 
Dll4MouseCalcification of Aortic Valve amelioratesIMP  RGD 
DLL4HumanPlaque, Atherosclerotic  ISODll4 (Mus musculus)protein:increased expression:aortaRGD 
Dll4RatPlaque, Atherosclerotic  ISODll4 (Mus musculus)protein:increased expression:aortaRGD 
Dll4MousePlaque, Atherosclerotic  IEP protein:increased expression:aortaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Dll4  (delta like canonical Notch ligand 4)

Genes (Mus musculus)
Dll4  (delta like canonical Notch ligand 4)

Genes (Homo sapiens)
DLL4  (delta like canonical Notch ligand 4)


Additional Information