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.
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.
|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|
|Westerterp, Marit; Bochem, Andrea E; Yvan-Charvet, Laurent et al. (2014) ATP-binding cassette transporters, atherosclerosis, and inflammation. Circ Res 114:157-70|
|Westerterp, Marit; Murphy, Andrew J; Wang, Mi et al. (2013) Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice. Circ Res 112:1456-65|
|Tolani, Sonia; Pagler, Tamara A; Murphy, Andrew J et al. (2013) Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children. Atherosclerosis 229:79-85|
|Nagareddy, Prabhakara R; Murphy, Andrew J; Stirzaker, Roslynn A et al. (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695-708|
|Murphy, Andrew J; Funt, Samuel; Gorman, Darren et al. (2013) Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity. Circ Res 113:e1-9|
|Murphy, Andrew J; Bijl, Nora; Yvan-Charvet, Laurent et al. (2013) Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis. Nat Med 19:586-94|
|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|