The ultimate treatment for coronary artery disease is the regression of the underlying atherosclerotic process. We have developed a novel mouse model for the study of regression in which plaques that developed into apoE-/- mice (high plasma non-HDL cholesterol (C), low HDL-C, absent apoE) are transplanted into wild type (WT) mice, which have low non-HDL-C, normal HDL-C, and normal apoE in their plasma. We have found that in the WT plasma environment, there is remarkable remodeling of the transplanted plaques over a relatively short time, with depletion of the majority of CD68+ cells (which are primarily macrophages and foam cells). Previous studies in WT recipients showed that the depletion of CD68+ cells reflected their emigration to lymph nodes, and required the upregulation of their chemokine receptor CCR7, a known migratory factor in monocyte-derived cells. Furthermore, the phenotypic state of the CD68+ cells shifted from an inflammatory (""""""""M1"""""""") to an anti-inflammatory one (""""""""M2""""""""). We hypothesize that each of the 3 plasma changes in the WT recipient contributes to the migratory and inflammatory properties of plaque CD68+ cells during regression. Because each plasma change promotes reverse cholesterol transport (RCT), a related hypothesis is that deficiency in macrophage RCT will compromise the ability of a plasma factor to influence CD68+ cell emigration and polarization to the M2 state. Two other hypotheses are that the transcriptional regulation of the migration factor CCR7 is regulated by the nuclear hormone receptor LXR and the sterol-regulated SREBP pathway (based on preliminary studies), and that the identification of the molecular processes central to the regression process in plaque CD68+ cells requires a systems biology approach that includes the meta- analyses of microarray and proteomic data across in vivo and in vitro studies. To test these hypotheses, there are 3 aims.
Aim 1 : To establish the roles of changes in plasma non-HDL-C, HDL-C, and apoE, and of RCT in atherosclerosis regression and phenotypic changes in plaque CD68+ cells;
Aim 2 : To determine the roles of LXR and SREBP in regulating CCR7 expression in vitro and in vivo;
Aim 3 : To employ a systems biology approach to identify the key molecular drivers of regression.

Public Health Relevance

The complications of atherosclerosis, coronary artery and cerebrovascular diseases, are major killers of the American population. Despite valuable benefits from current therapeutics, there is still considerable residual risk to the population. Learning more about how atherosclerotic plaques regress will likely lead to new therapeutic and diagnostic clinical strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084312-08
Application #
8434921
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2006-04-01
Project End
2014-11-30
Budget Start
2013-03-01
Budget End
2014-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$618,955
Indirect Cost
$205,483
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Amengual, Jaume; Guo, Liang; Strong, Alanna et al. (2018) Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100. Circ Res 122:568-582
Moore, Kathryn J; Koplev, Simon; Fisher, Edward A et al. (2018) Macrophage Trafficking, Inflammatory Resolution, and Genomics in Atherosclerosis: JACC Macrophage in CVD Series (Part 2). J Am Coll Cardiol 72:2181-2197
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Rahman, Karishma; Fisher, Edward A (2018) Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression. Front Cardiovasc Med 5:32
Loke, P'ng; Niewold, Timothy B (2017) By CyTOF: Heterogeneity of Human Monocytes. Arterioscler Thromb Vasc Biol 37:1423-1424
Yu, Mikyung; Amengual, Jaume; Menon, Arjun et al. (2017) Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr-/- Mice. Adv Healthc Mater 6:
Barrett, Tessa J; Murphy, Andrew J; Goldberg, Ira J et al. (2017) Diabetes-mediated myelopoiesis and the relationship to cardiovascular risk. Ann N Y Acad Sci 1402:31-42
Harris, Nicola L; Loke, P'ng (2017) Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection. Immunity 47:1024-1036
Ruparelia, Neil; Chai, Joshua T; Fisher, Edward A et al. (2017) Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 14:133-144
Arlauckas, Sean P; Garris, Christopher S; Kohler, Rainer H et al. (2017) In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med 9:

Showing the most recent 10 out of 76 publications