PMID- 22699504
OWN - NLM
STAT- MEDLINE
DCOM- 20120918
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 109
IP  - 27
DP  - 2012 Jul 3
TI  - Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic 
      disorders.
PG  - E1868-77
LID - 10.1073/pnas.1116889109 [doi]
AB  - 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-kappaB (NF-kappaB) 
      activation. In vitro cell culture experiments revealed that Dll4-mediated Notch 
      signaling increases MCP-1 expression via NF-kappaB, 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.
FAU - Fukuda, Daiju
AU  - Fukuda D
AD  - Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 
      Boston, MA 02115, USA.
FAU - Aikawa, Elena
AU  - Aikawa E
FAU - Swirski, Filip K
AU  - Swirski FK
FAU - Novobrantseva, Tatiana I
AU  - Novobrantseva TI
FAU - Kotelianski, Victor
AU  - Kotelianski V
FAU - Gorgun, Cem Z
AU  - Gorgun CZ
FAU - Chudnovskiy, Aleksey
AU  - Chudnovskiy A
FAU - Yamazaki, Hiroyuki
AU  - Yamazaki H
FAU - Croce, Kevin
AU  - Croce K
FAU - Weissleder, Ralph
AU  - Weissleder R
FAU - Aster, Jon C
AU  - Aster JC
FAU - Hotamisligil, Gokhan S
AU  - Hotamisligil GS
FAU - Yagita, Hideo
AU  - Yagita H
FAU - Aikawa, Masanori
AU  - Aikawa M
LA  - eng
GR  - R01 HL095612/HL/NHLBI NIH HHS/United States
GR  - R01 HL107550/HL/NHLBI NIH HHS/United States
GR  - R01HL107550/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120613
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibodies, Neutralizing)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (DLL4 protein, human)
RN  - 0 (DLL4 protein, mouse)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, LDL)
RN  - 0 (Receptors, Notch)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adaptor Proteins, Signal Transducing
MH  - Adipocytes/cytology/metabolism
MH  - Adipose Tissue/metabolism
MH  - Animals
MH  - Antibodies, Neutralizing/*pharmacology
MH  - Aortic Valve Insufficiency/immunology/metabolism
MH  - Atherosclerosis/immunology/*metabolism/therapy
MH  - Calcium-Binding Proteins
MH  - Chemokine CCL2/metabolism
MH  - Endothelial Cells/cytology/metabolism
MH  - Humans
MH  - Immunity, Innate/physiology
MH  - Insulin Resistance/physiology
MH  - Intercellular Signaling Peptides and Proteins/immunology/*metabolism
MH  - Intracellular Signaling Peptides and Proteins/genetics/immunology/*metabolism
MH  - Macrophages/immunology/metabolism
MH  - Membrane Proteins/genetics/immunology/*metabolism
MH  - Metabolic Syndrome/immunology/*metabolism/therapy
MH  - Mice
MH  - Mice, Obese
MH  - Mice, Transgenic
MH  - Receptors, LDL/genetics
MH  - Receptors, Notch/metabolism
MH  - Saphenous Vein/cytology
MH  - Signal Transduction/physiology
PMC - PMC3390871
COIS- The authors declare no conflict of interest.
EDAT- 2012/06/16 06:00
MHDA- 2012/09/19 06:00
PMCR- 2013/01/03
CRDT- 2012/06/16 06:00
PHST- 2012/06/16 06:00 [entrez]
PHST- 2012/06/16 06:00 [pubmed]
PHST- 2012/09/19 06:00 [medline]
PHST- 2013/01/03 00:00 [pmc-release]
AID - 1116889109 [pii]
AID - 201116889 [pii]
AID - 10.1073/pnas.1116889109 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2012 Jul 3;109(27):E1868-77. doi: 
      10.1073/pnas.1116889109. Epub 2012 Jun 13.