Anti-atherogenic functions of HDL cholesterol include mediation of reverse cholesterol transport as well as anti-oxidant and anti-inflammatory effects. Scavenger receptor class B type-l (SR-BI) and apolipoprotein E (apoE) both play crucial roles in HDL metabolism and reverse cholesterol transport. Combined deficiency of SR-BI and apoE (DKO) in mice results in dyslipidemia, characterized by large free cholesterol (FC)-enriched HDL particles, accelerated occlusive coronary disease, and premature death due to myocardial infarction. Our preliminary studies show that DKO HDL particles may be dysfunctional and proatherogenic by inducing FC overload in wild type macrophages.
In Specific Aim (SA) 1, we will examine the hypothesis that the DKO HDL cholesterol particles are severely dysfunctional and proatherogenic, promoting oxidation, inflammation, and abnormal reverse cholesterol transport. ApoE may mediate RCT through both SR-BI dependent and independent pathways, and the loss of both pathways may contribute to the lethal phenotype in DKO mice. Macrophage-specific deletion of either apoE or SR-BI promotes atherosclerosis. Our preliminary studies indicate that macrophage deficiency of both apoE and SR-BI results in dramatically impaired cholesterol homeostasis and a striking increase in accumulation of apoptotic cells in atherosclerotic lesions, independent of the DKO lipid environment. These results suggest that DKO macrophages may be prone to FC-induced apoptosis and/or impaired phagocytic clearance of apoptotic cells in atherosclerosis. The goal of SA2 is to test the hypothesis that macrophage apoE and SR-BI cooperate to limit atherogenesis and apoptosis. The abnormal cholesterol homeostasis of DKO macrophages suggests that SR-BI and apoE function in a cooperative fashion to optimize macrophage trafficking and mobilization of cholesterol. In SA3, in vitro studies will examine the hypothesis that SR-BI-associated cholesterol domains and signaling modulate apoE secretion. Studies will also test the hypothesis that apoE containing HDL are the most efficient acceptors of SR-BI mobilized cholesterol. Finally, we will examine the hypothesis that SR-BI and apoE expression impact ABCA1- and ABCG1-mediated trafficking and mobilization of cholesterol. New insights into the roles of apoE and SR-BI as determinants of the anti-atherogenic functions of HDL cholesterol and macrophage cholesterol homeostasis and apoptosis may lead to new therapeutic approaches for atherosclerosis. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL086988-01A1
Application #
7321215
Study Section
Special Emphasis Panel (ZRG1-CVS-Q (02))
Program Officer
Wassef, Momtaz K
Project Start
2007-09-01
Project End
2011-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$383,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Tao, Huan; Yancey, Patricia G; Babaev, Vladimir R et al. (2015) Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. J Lipid Res 56:1449-60
Fazio, Sergio; Linton, MacRae F (2012) Inhibition of apolipoprotein(a) synthesis by farnesoid X receptor and fibroblast growth factor 15/19: a step toward selective lipoprotein(a) therapeutics. Arterioscler Thromb Vasc Biol 32:1060-2
Sampson, Uchechukwu K; Fazio, Sergio; Linton, MacRae F (2012) Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 14:1-10
Woo, Kel Vin; Qu, Xianghu; Babaev, Vladimir R et al. (2011) Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress-specific manner. J Clin Invest 121:1624-35
Yancey, Patricia G; Ding, Yu; Fan, Daping et al. (2011) Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6Chigh monocytosis: evidence that the effects are not apolipoprotein E dependent. Circulation 124:454-64
Sampson, Uchechukwu K; Linton, Macrae F; Fazio, Sergio (2011) Are statins diabetogenic? Curr Opin Cardiol 26:342-7
Babaev, Vladimir R; Whitesell, Richard R; Li, Liying et al. (2011) Selective macrophage ascorbate deficiency suppresses early atherosclerosis. Free Radic Biol Med 50:27-36
Babaev, Vladimir R; Li, Liying; Shah, Sanket et al. (2010) Combined vitamin C and vitamin E deficiency worsens early atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 30:1751-7
Linton, Macrae F; Fazio, Sergio (2010) 6-Mercaptopurine, monocytes, and atherosclerosis. Arterioscler Thromb Vasc Biol 30:1494-6
Lewis, Terry L; Cao, Dongfeng; Lu, Hailin et al. (2010) Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem 285:36958-68

Showing the most recent 10 out of 19 publications