Accelerated atherosclerosis displays a complex pathogenesis including alterations in lipids, inflammatory state involving the immune system. HDL apoA-I protects against these changes mainly through its ability to organize and recruit cholesterol and oxygenated forms of cholesterol and phospholipids from immune cells protecting them from dysregulation and apoptosis. In the current proposal, we will investigate the molecular mechanisms responsible for immune cell cholesterol deposition, accelerated atherosclerosis and the development of an autoimmune phenotype in response to an atherogenic diet in LDL receptor, apoA-Idouble knockout (DKO) mice. In previous studies, when DKO and LDLr-/- (SKO) mice were fed an atherogenic diet, DKO mice developed enlarged peripheral lymph nodes (LNs) and spleens compared to SKO mice. DKO LN were enriched in cholesterol ester (CE) and contained expanded populations of CE enriched T, B, dendritic cells and macrophages. Plasma antibodies to dsDNA and oxidized LDL were also increased in DKO suggesting an autoimmune phenotype. Both LN enlargement and LN CE accumulation were "prevented" when diet-fed DKO mice were treated with apoA-I at the time the diet was initiated. Regardless of the level of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation. Therefore, the goal of this proposal is to use the DKO mouse to investigate the mechanisms by which apoA-I 1) modulates CE and oxysterol accumulation and activation in lymphocytes, 2) alters the proliferation and/or apoptosis of CE loaded lymphocytes, 3) affects the contribution of T cells and DC to plaque infiltration in both progression and regression of atherosclerosis in diet-fed DKO mice.

Public Health Relevance

Atherosclerosis is a chronic inflammatory disease that is initiated by cellular cholesterol dysregulation at the vessel wall. Our proposed studies will investigate the mechanisms explaining the role of apoA-I in regulating lymphocyte cholesterol homeostasis, autoimmunity and atherosclerosis. These studies will likely provide new targets for therapeutic interventions to control the inflammatory processes that exacerbate atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064163-11
Application #
8206793
Study Section
Special Emphasis Panel (ZRG1-VH-D (02))
Program Officer
Liu, Lijuan
Project Start
1999-12-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
11
Fiscal Year
2012
Total Cost
$366,300
Indirect Cost
$118,800
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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Bhat, Shaila; Sorci-Thomas, Mary G; Calabresi, Laura et al. (2010) Conformation of dimeric apolipoprotein A-I milano on recombinant lipoprotein particles. Biochemistry 49:5213-24
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Sorci-Thomas, Mary G; Bhat, Shaila; Thomas, Michael J (2009) Activation of lecithin:cholesterol acyltransferase by HDL ApoA-I central helices. Clin Lipidol 4:113-124
Thomas, Michael J; Bhat, Shaila; Sorci-Thomas, Mary G (2008) Three-dimensional models of HDL apoA-I: implications for its assembly and function. J Lipid Res 49:1875-83

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