Abstract
Objective-Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results-We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage-or endothelial cell (EC)-targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion development in low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation. Conclusions-These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4-Notch axis as a novel therapeutic target.
| Original language | English |
|---|---|
| Pages (from-to) | 2343-2353 |
| Number of pages | 11 |
| Journal | Arteriosclerosis, thrombosis, and vascular biology |
| Volume | 35 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 1 2015 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
Cite this
Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development : Implications for the Treatment of Vein Graft Failure. / Koga, Jun Ichiro; Nakano, Toshiaki; Dahlman, James E.; Figueiredo, Jose Luiz; Zhang, Hengmin; Decano, Julius; Khan, Omar F.; Niida, Tomiharu; Iwata, Hiroshi; Aster, Jon C.; Yagita, Hideo; Anderson, Daniel G.; Keith Ozaki, C.; Aikawa, Masanori.
In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 35, No. 11, 01.11.2015, p. 2343-2353.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development
T2 - Implications for the Treatment of Vein Graft Failure
AU - Koga, Jun Ichiro
AU - Nakano, Toshiaki
AU - Dahlman, James E.
AU - Figueiredo, Jose Luiz
AU - Zhang, Hengmin
AU - Decano, Julius
AU - Khan, Omar F.
AU - Niida, Tomiharu
AU - Iwata, Hiroshi
AU - Aster, Jon C.
AU - Yagita, Hideo
AU - Anderson, Daniel G.
AU - Keith Ozaki, C.
AU - Aikawa, Masanori
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Objective-Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results-We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage-or endothelial cell (EC)-targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion development in low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation. Conclusions-These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4-Notch axis as a novel therapeutic target.
AB - Objective-Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results-We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage-or endothelial cell (EC)-targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft lesion development in low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced lesion development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation. Conclusions-These results suggest that macrophage Dll4 promotes lesion development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4-Notch axis as a novel therapeutic target.
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UR - http://www.scopus.com/inward/citedby.url?scp=84945477836&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.115.305516
DO - 10.1161/ATVBAHA.115.305516
M3 - Article
C2 - 26404485
AN - SCOPUS:84945477836
VL - 35
SP - 2343
EP - 2353
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 11
ER -