Coronary plaques begin their progression in childhood, making their reversal an important clinical goal in adulthood. The understanding of mechanisms underlying atherosclerosis regression has been understudied compared to plaque progression. Atherosclerosis represents a failure to resolve the maladaptive immune response that maintains plaque growth through the accumulation of pro-inflammatory immune cells. The central inflammatory cell in the plaque is the macrophage (M) in the activated state. We previously showed that plaque regression in mouse models is characterized by the enrichment of Ms in the inflammation resolving state (which we will refer to as proR-Ms). We have recently shown that these proR-Ms are required for regression. We also have observed in regressing plaques increased numbers of inflammation dampening CD4+ regulatory T cells (Tregs), which prevent the expansion of effector T cells and support proR-M functions. Furthermore, our results point to Wnt-signaling and chemokine receptor CCR7 as key pathways associated with a pro-resolving environment. We hypothesize that all of these factors play important roles in the reprogramming of the plaque inflammatory milieu to enable inflammation tissue repair in the artery wall and thereby promote atherosclerosis regression. The development of novel therapies for atherosclerosis must also take into account ?real world? clinical issues. Accumulating data now show that the majority of treated patients intermittently adhere to statins, which increases their CAD risk. We hypothesize that epigenetic reprogramming of macrophages and their precursors by IH through trained immunity mediates these adverse effects on atherosclerosis, further hindering inflammation resolution and rendering plaques susceptible to accelerated disease and refractory to regression. We have developed the following specific aims to investigate the factors and pathways that drive or hinder inflammation resolution and plaque remodeling during atherosclerosis regression:
Aim 1 : To study the regulation of the inflammation-resolving properties of plaque Ms by Wnt-signaling.
Aim 2 : To determine the role of CCR7 in the resolution of atherosclerotic inflammation and plaque regression.
Aim 3 : To establish the mechanistic basis for increased coronary artery disease risk in patients with intermittent statin adherence. In summary, this proposal represents an exciting opportunity to continue to combine our collective expertises to address crucial gaps in our knowledge of the resolution of inflammation in atherosclerosis.

Public Health Relevance

Atherosclerosis is a disease in which plaques with inflammatory cells accumulate in arteries. People at risk for heart attacks only partially benefit from current treatments to prevent the clinical events these plaques cause. To effectively reverse plaques, their inflammation must resolve, and ways to achieve this are the focus of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL084312-13
Application #
10220409
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2006-04-01
Project End
2025-02-28
Budget Start
2021-03-20
Budget End
2022-02-28
Support Year
13
Fiscal Year
2021
Total Cost
Indirect Cost
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
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:
Rahman, Karishma; Vengrenyuk, Yuliya; Ramsey, Stephen A et al. (2017) Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest 127:2904-2915

Showing the most recent 10 out of 76 publications