Despite the success of LDL lowering therapies there is a need for new treatments to reduce the large burden of residual atherosclerotic cardiovascular disease. Increasing beneficial HDL functions is one potential approach. HDL infusion therapies and small molecule LXR activators, induce cholesterol efflux from macrophage foam cells and reduce atherosclerosis in animal models. However, the underlying protective mechanisms are incompletely understood and this has delayed clinical development. Cholesterol efflux pathways appear to exert anti-atherogenic effects by suppressing inflammatory responses in myeloid cells. The efflux of cholesterol to ApoA-1 and HDL is facilitated by the ATP binding cassette transporters ABCA1 and ABCG1, which are induced by LXRs. Our recent studies in mice with myeloid cell deficiency of these transporters have revealed a major role of cholesterol efflux pathways in suppressing the inflammasome. These mice showed inflammasome activation in macrophages and neutrophils. Unexpectedly, they also displayed prominent neutrophil extracellular traps (NETs) in lesions. Deficiency of inflammasome components reduced lesion area and abolished NETs, showing for the first time that inflammasome activation promotes lesional NETosis. The recent CANTOS trial has highlighted the importance of inflammasome activation and IL-1b production in human coronary heart disease. Other studies have shown a role of NETosis in atherogenesis and plaque instability. Thus, our studies showing that HDL and cholesterol efflux pathways can suppress these processes have major translational potential, especially in conditions where ABCA1/G1 are suppressed and HDL levels are low, such as Type 2 diabetes. The goal of this proposal is to evaluate mechanisms linking cholesterol efflux pathways to atherogenic inflammation.
Aim 1 will explore mechanisms linking ABCA1/G1-mediated cholesterol efflux to inflammasome activation, atherogenesis and NETosis.
Aim 2 will explore the mechanisms and significance of rHDL- mediated cholesterol efflux in macrophage inflammation.
Aim 3 will assess new mechanisms connecting LXR activation to suppression of atherogenic inflammation. These studies may provide novel mechanistic insights stimulating the development of new treatments for atherosclerosis.

Public Health Relevance

This study will examine mechanisms linking HDL-mediated cholesterol efflux to atherosclerosis, particularly the role of cholesterol efflux pathways in suppressing inflammasome activation and neutrophil extracellular trap formation in atherosclerotic plaques. This work may provide novel mechanistic insights stimulating the development of new treatments for atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107653-10
Application #
9889981
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2011-06-01
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Westerterp, Marit; Fotakis, Panagiotis; Ouimet, Mireille et al. (2018) Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis. Circulation 138:898-912
Wang, Wei; Liu, Wenli; Fidler, Trevor et al. (2018) Macrophage Inflammation, Erythrophagocytosis, and Accelerated Atherosclerosis in Jak2 V617F Mice. Circ Res 123:e35-e47
Westerterp, Marit; Gautier, Emmanuel L; Ganda, Anjali et al. (2017) Cholesterol Accumulation in Dendritic Cells Links the Inflammasome to Acquired Immunity. Cell Metab 25:1294-1304.e6
Ganda, Anjali; Yvan-Charvet, Laurent; Zhang, Yuan et al. (2017) Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD. J Mol Cell Cardiol 112:114-122
Wang, Ying; Wang, Wei; Wang, Nan et al. (2017) Mitochondrial Oxidative Stress Promotes Atherosclerosis and Neutrophil Extracellular Traps in Aged Mice. Arterioscler Thromb Vasc Biol 37:e99-e107
Libby, Peter; Bornfeldt, Karin E; Tall, Alan R (2016) Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res 118:531-4
Wang, Nan; Tall, Alan R (2016) Cholesterol in platelet biogenesis and activation. Blood 127:1949-53
Wang, Wei; Tang, Yang; Wang, Ying et al. (2016) LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis. Circ Res 119:e91-e103
Westerterp, Marit; Wang, Nan; Tall, Alan R (2016) High-Density Lipoproteins, Endothelial Function, and Mendelian Randomization. Circ Res 119:13-5

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