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
Wang, Mi; Subramanian, Manikandan; Abramowicz, Sandra et al. (2014) Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion, monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency. Arterioscler Thromb Vasc Biol 34:976-84
Kappus, Mojdeh S; Murphy, Andrew J; Abramowicz, Sandra et al. (2014) Activation of liver X receptor decreases atherosclerosis in Ldlrýýý/ýýý mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. Arterioscler Thromb Vasc Biol 34:279-84
Murphy, Andrew J; Tall, Alan R (2014) Proliferating macrophages populate established atherosclerotic lesions. Circ Res 114:236-8
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Murphy, Andrew J; Akhtari, Mani; Tolani, Sonia et al. (2011) ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest 121:4138-49