Plasma high density lipoproteins (HDL) have an inverse relationship to the incidence of atherosclerotic cardiovascular disease (CVD) but the mechanisms underlying this relationship are incompletely understood. A central anti-atherogenic effect of HDL is believed to be mediated by cholesterol efflux from atheromatous macrophage foam cells to HDL or apoA-1, a process mediated in part by the ATP binding cassette transporters ABCA1 and ABCG1. Recent work in this project has uncovered a new function of HDL and these ABC transporters: the promotion of cholesterol efflux from hematopoietic stem and progenitor cells (HSPCs). Cholesterol efflux from HSPCs has an important role in controlling their proliferative response to growth factors such as IL-3 and GM-CSF. Proliferation of HSPCs in mice lacking ABCA1/G1 leads to leukocytosis, monocytosis and accelerated atherosclerosis. The proposed studies will examine the mechanisms underlying this enhanced proliferation, such as increased cell surface levels of the GM-CSF/IL-3 receptor on HSPCs. A possible role of micro-RNA-33 in mediating growth factor suppression of ABCA1/G1 will be examined with Dr. Moore. Also, the studies will employ recently developed Abca1fl/flAbcg1fl/fl mice that will be crossed with various Cre-expressing strains to examine the separate roles of decreased transporter expression in foam cells, HSPCs and dendritic cells in the production of accelerated atherosclerosis. In collaboration with Dr. Fisher, we will also use these mouse models to examine the role of transporters in facilitating regression of atherosclerosis.

Public Health Relevance

We are proposing a novel mechanism for the athero-protective effect of HDL in which HDL acting in conjunction with ABC transporters promotes cholesterol efflux and suppresses proliferation of hematopoietic stem cells. These studies will likely help to establish a link between stem cell proliferation and the well known leukocytosis and monocytosis associated with atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107653-03
Application #
8465264
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Liu, Lijuan
Project Start
2011-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$383,180
Indirect Cost
$145,180
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
Westerterp, Marit; Wang, Nan; Tall, Alan R (2016) High-Density Lipoproteins, Endothelial Function, and Mendelian Randomization. Circ Res 119:13-5
Zimmer, Sebastian; Grebe, Alena; Bakke, Siril S et al. (2016) Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med 8:333ra50
Wang, Wei; Tang, Yang; Wang, Ying et al. (2016) LNK/SH2B3 Loss of Function Promotes Atherosclerosis and Thrombosis. Circ Res 119:e91-e103
Murphy, Andrew J; Tall, Alan R (2016) Disordered haematopoiesis and athero-thrombosis. Eur Heart J 37:1113-21
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
Westerterp, Marit; Tsuchiya, Kyoichiro; Tattersall, Ian W et al. (2016) Deficiency of ATP-Binding Cassette Transporters A1 and G1 in Endothelial Cells Accelerates Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol 36:1328-37
Tall, Alan R; Yvan-Charvet, Laurent (2015) Cholesterol, inflammation and innate immunity. Nat Rev Immunol 15:104-16
Bochem, Andrea E; van der Valk, Fleur M; Tolani, Sonia et al. (2015) Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins. Arterioscler Thromb Vasc Biol 35:1663-9
Murphy, Andrew J; Tall, Alan R (2014) Proliferating macrophages populate established atherosclerotic lesions. Circ Res 114:236-8

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