Macrophage endoplasmic reticulum (ER) stress in regulating the pathogenesis of atherosclerosis is not fully understood. The central goal of this proposal is to examine the role of RTN-4B (aka, Nogo-B), an integral membrane protein mainly localized to the ER, in macrophage ER stress and atherosclerosis. We have shown that Nogo-B is highly abundant in endothelial cells (EC), vascular smooth muscle cells (VSMC) and monocytes/macrophages with diverse and cell-specific function. The genetic loss of Nogo-B (Nogo-/-) results in exaggerated neointima formation after arterial injury and impaired blood flow recovery post-ischemia. Nogo-B regulates acute inflammatory response in EC and suppresses hypoxia-induced pulmonary VSMC apoptosis. In humans, the expression of Nogo-B negatively correlates with the severity of atherosclerosis, suggests that the local reduction of Nogo-B might contribute to plaque formation and/or instability. Our exciting preliminary data demonstrate that Nogo-/- mice on an ApoE knockout background (ApoE-/-Nogo-/-) develop larger and more advanced atherosclerotic lesions with increased macrophage apoptosis compared to ApoE-/- mice. The ApoE-/-Nogo-/- mice also developed severe coronary stenosis, a phenotype that is rarely observed in current mouse models of atherosclerosis. Nogo-/- macrophages are much more prone to apoptosis in response to free cholesterol loading compared to those of wild-type mice. We also show that Nogo-B can be secreted and transferred from ECs to macrophages and that exogenous Nogo-B can prevent macrophage apoptosis. We hypothesize that Nogo-B governs macrophage functions to regulate atherosclerotic plaque formation and necrosis. In this proposal, we will: (1) define the role of macrophage Nogo-B in atherosclerotic plaque progression and necrosis in vivo, (2) elucidate the mechanisms by which cell intrinsic Nogo-B regulates ER stress induced macrophage apoptosis in vitro, and (3) examine the non-cell-autonomous effects of Nogo-B in macrophage functions. The findings of this study will advance the Nogo field, providing insights in understanding how Nogo regulate vascular homeostasis.

Public Health Relevance

Atherosclerotic plaque rupture is the most common cause of cardiac events, which lead to the most death in the world. Our research has discovered a new modulator (RTN-4B) of atherosclerotic plaque progression and necrosis. The main goal of this proposal is to examine the role of RTN-4B in atherosclerosis. Research supported by this grant may help identify potential therapeutic strategies for regulating macrophage function in the artery wall, which may prevent mobility and mortality of patients with cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL117064-01A1
Application #
8732749
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
2013-09-20
Project End
2014-08-31
Budget Start
2013-09-20
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$416,250
Indirect Cost
$166,250
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520