One of the key events in atherogenesis is the accumulation of cholesteryl (Chol) ester-laden macrophages (MOs) or foam cells, which contribute to both early and late lesion complications. Previous studies have elucidated two key steps in MO foam cell formation: binding and internalization of atherogenic lipoproteins (LPs), and stimulation of the intracellular Chol esterification pathway. The overall objective of this proposal is to explore novel hypotheses regarding each of these steps. The first step, binding and internalization, is usually studied by incubating cultured MOs with soluble, monomeric LPs. In actual atherosclerotic lesions, however, most LPs are avidly bound to subendothelial matrix, and many are in an aggregated or fused state. In this light, the overall working hypothesis of Aim I is that certain critical cellular processes involved in the interaction of MOs with retained and aggregated LPs-the likely in vivoprocess-are fundamentally different from those that occur when MOs encounter soluble, monomeric LPs-the typical in vitro experimental system. Based upon preliminary data using an experimental cell culture system in which MOs are added to matrix-retained and aggregated LDL, we will focus on specific hypotheses related to four processes: receptor interaction, trafficking of protein and Cholesterol moieties of LDL, MO actin signaling pathways, and MO secretory responses. We hypothesize that (a) the early phases of this interaction involve a change in receptor recognition and differential trafficking of LDL-protein vs. LDL-Chol; and (b) the later phases involve actin remodeling events and secretory responses that are similar to those that occur during certain types of phagocytosis. The second critical step in foam cell formation, Chol esterification, is triggered when cellular Chol levels reach a threshold level. The key regulatory step appears to be the transfer of Chol from the plasma membrane (PM) to internal membranes containing acyl-CoA:cholesterol acyltransferase (ACAT), but very little is known about the cellular mechanisms involved.
In Aim LI, we will explore the hypothesis that the stimulation of Chol esterification that is triggered at Chol threshold is associated with a phase change in the PM, which induces an increase in PM-to-ACAT Chol transport. To accomplish this goal, we will use newly refined imaging techniques that allow one to accurately follow plasma membrane phase changes and sterol trafficking in cells. In summary, these studies should elucidate novel molecular and cellular mechanisms involved in MO foam cell formation and thus provide new insights into this critical cellular event of atherogenesis.
|Zhou, Alex-Xianghua; Wang, Xiaobo; Lin, Chyuan Sheng et al. (2015) C/EBP-Homologous Protein (CHOP) in Vascular Smooth Muscle Cells Regulates Their Proliferation in Aortic Explants and Atherosclerotic Lesions. Circ Res 116:1736-43|
|Tabas, Ira; Glass, Christopher K (2013) Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339:166-72|
|Woo, Connie W; Kutzler, Lydia; Kimball, Scot R et al. (2012) Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B. Nat Cell Biol 14:192-200|
|Moore, Kathryn J; Tabas, Ira (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145:341-55|
|Ouimet, Mireille; Franklin, Vivian; Mak, Esther et al. (2011) Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab 13:655-67|
|Shechtman, Caryn F; Henneberry, Annette L; Seimon, Tracie A et al. (2011) Loss of subcellular lipid transport due to ARV1 deficiency disrupts organelle homeostasis and activates the unfolded protein response. J Biol Chem 286:11951-9|
|Devlin, Cecilia; Pipalia, Nina H; Liao, Xianghai et al. (2010) Improvement in lipid and protein trafficking in Niemann-Pick C1 cells by correction of a secondary enzyme defect. Traffic 11:601-15|
|Thorp, Edward; Li, Gang; Seimon, Tracie A et al. (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metab 9:474-81|
|Haka, Abigail S; Grosheva, Inna; Chiang, Ethan et al. (2009) Macrophages create an acidic extracellular hydrolytic compartment to digest aggregated lipoproteins. Mol Biol Cell 20:4932-40|
|Manning-Tobin, Jennifer J; Moore, Kathryn J; Seimon, Tracie A et al. (2009) Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc Biol 29:19-26|
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