This multidisciplinary research project will test the novel hypothesis that Dll4-triggered signaling contributes to the pathogenesis of atherosclerosis. We will focus on macrophage-derived proteolytic activity, the key feature typical of arterial remodeling associated with the onset of acute coronary events. We previously reported that Dll4 (a ligand of Notch signaling) promotes expression or activation of pro-inflammatory factors (e.g., iNOS, NF-?B) in cultured macrophages. The role of Notch signaling is strictly cell-type- and context- dependent, and in vivo functions of the Notch pathway in macrophages remain unknown. Using mouse models, the present study will explore the role of the Dll4-Notch axis in activation of plaque macrophages and development of atherosclerosis.
Specific Aim 1 will examine whether Dll4 antibody administration attenuates macrophage activation and atherogenesis in Ldlr-/- mice. We will also use macrophage-targeted in vivo delivery of Dll4 siRNA to determine the relative contribution of macrophage Dll4.
Specific Aim 2 will address the role of Notch3 based on our data that suggested its pro-atherogenic role. In Notch3-transgenic and null mice to test the hypothesis that this Notch receptor promotes macrophage activation and athrogenesis. These complementary studies will offer novel mechanisms of macrophage activation and atherosclerosis, and will also provide proof of concept that the Dll4-Notch3 pathway can be a therapeutic target for atherosclerosis, its complications, and other vascular diseases.

Public Health Relevance

Inflammation in coronary arteries triggers acute complications of atherosclerosis (e.g., heart attack). However, the mechanism for arterial inflammation remains incompletely understood. We previously used cell culture systems that Delta-like 4 (Dll4) triggers inflammation. The present study will perform mouse experiments to dissect the new mechanisms of inflammation and atherosclerosis. The potential outcomes will offer new therapeutic targets for vascular diseases and contribute to preventive cardiovascular medicine.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107550-03
Application #
8585087
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kirby, Ruth
Project Start
2012-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$490,381
Indirect Cost
$141,503
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Goettsch, Claudia; Hutcheson, Joshua D; Aikawa, Masanori et al. (2016) Sortilin mediates vascular calcification via its recruitment into extracellular vesicles. J Clin Invest 126:1323-36
Goettsch, Claudia; Hutcheson, Joshua D; Hagita, Sumihiko et al. (2016) A single injection of gain-of-function mutant PCSK9 adeno-associated virus vector induces cardiovascular calcification in mice with no genetic modification. Atherosclerosis 251:109-18
Singh, Sasha A; Andraski, Allison B; Pieper, Brett et al. (2016) Multiple apolipoprotein kinetics measured in human HDL by high-resolution/accurate mass parallel reaction monitoring. J Lipid Res 57:714-28
Iwata, Hiroshi; Goettsch, Claudia; Sharma, Amitabh et al. (2016) PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nat Commun 7:12849
Nakano, Toshiaki; Fukuda, Daiju; Koga, Jun-Ichiro et al. (2016) Delta-Like Ligand 4-Notch Signaling in Macrophage Activation. Arterioscler Thromb Vasc Biol 36:2038-47
Shibasaki, Manabu; Wang, Jian-Guo; Figueiredo, Jose-Luiz et al. (2015) Pitavastatin Reduces Inflammation in Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice with Late Stage Renal Disease. PLoS One 10:e0138047
Lu, Hong; Aikawa, Masanori (2015) Many faces of matrix metalloproteinases in aortic aneurysms. Arterioscler Thromb Vasc Biol 35:752-4
Koga, Jun-ichiro; Nakano, Toshiaki; Dahlman, James E et al. (2015) Macrophage Notch Ligand Delta-Like 4 Promotes Vein Graft Lesion Development: Implications for the Treatment of Vein Graft Failure. Arterioscler Thromb Vasc Biol 35:2343-53
Figueiredo, Jose-Luiz; Aikawa, Masanori; Zheng, Chunyu et al. (2015) Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease. Am J Pathol 185:1156-66
Koga, Jun-ichiro; Aikawa, Masanori (2014) Application of anti-ligand antibodies to inhibit Notch signaling. Methods Mol Biol 1187:335-42

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