Apolipoprotein (apo) Al is the main structural component of plasma HDL. Plasma levels of HDL and apoAl are inversely related to CHD rates, and their manipulation is a therapeutic intervention for atherosclerosis. ApoAl is the driver of reverse cholesterol transport (RCT), the pathway through which excess peripheral cholesterol is delivered to the hepatocyte. The mechanism through which RCT promotes vascular health is not understood, and the possibility exists that apoAl and HDL exert direct protective effects in the artery wall. In this light, higher HDL levels might simply be related to higher concentrations of HDL in the artery wall, which may be the true effector of plaque stabilization. In the previous cycle of this grant we have shown that the exclusive production of apoAl from arterial macrophages leads to high concentrations of apoAl in the plaque, with minimal amounts of apoAl in plasma and no changes in plasma HDL. This intervention resulted in the complete prevention of atherosclerosis in mouse models with different levels of plasma HDL, ranging from almost none to twice normal. We have also shown that arterial expression of apoAl significantly reduces the atherogenesis induced by apoE deficiency, suggesting that macrophage apoAl can counter heavy lipid burden. We have accomplished this through a combined approach of transgenic, macrophage-specific apoAl expression, and bone marrow cell transduction using apoAI-expressing retroviral vectors. We are now proposing the natural progression of these investigative lines, aiming for mechanistic discoveries, technical innovation, and clinical translatability. We will develop lentiviral vectors expressing apoAl constructs driven by the physiologic ME2 promoter, which is sensitive to cholesterol loading through the physiologic LXR loop. In this system, macrophage-specific expression of apoAl will be up-regulated during the transformation of the macrophage into a foam cell. We will also produce transgenic mice that express apoAl driven by the same cholesterol-sensitive promoter. Another technological advance will be the use of purified hematopoietic stem cells (HSC) and sub-lethal doses of radiation. Using these tools, we will evaluate the effects of human apoAl and single amino-acid variants on vascular lipid accumulation and inflammation in vivo and in vitro. The natural apoAl variants are known to lower HDL levels with diverging effects on atherogenesis. The main hypotheses to be tested are: 1) The vascular effects of apoAl can be dissociated from plasma HDL levels; 2) ApoAl has direct effects on macrophage cholesterol homeostasis, inflammation, and oxidation. These studies have the potential to uncover the basis for the therapeutic effect of HDL on the arterial plaque. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065709-09
Application #
7446115
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
2000-07-01
Project End
2009-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
9
Fiscal Year
2008
Total Cost
$362,679
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
Kaseda, Ryohei; Jabs, Kathy; Hunley, Tracy E et al. (2015) Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism 64:263-73
Yamamoto, Suguru; Zhong, Jiayong; Yancey, Patricia G et al. (2015) Atherosclerosis following renal injury is ameliorated by pioglitazone and losartan via macrophage phenotype. Atherosclerosis 242:56-64
Yamamoto, Suguru; Yancey, Patricia G; Ikizler, T Alp et al. (2012) Dysfunctional high-density lipoprotein in patients on chronic hemodialysis. J Am Coll Cardiol 60:2372-9
Levin, M C; Lidberg, U; Jirholt, P et al. (2012) Evaluation of macrophage-specific promoters using lentiviral delivery in mice. Gene Ther 19:1041-7
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
Rana, Tanu; Misra, Smita; Mittal, Mukul K et al. (2011) Mechanism of down-regulation of RNA polymerase III-transcribed non-coding RNA genes in macrophages by Leishmania. J Biol Chem 286:6614-26
Sampson, Uchechukwu K; Perati, Prudhvidhar R; Prins, Petra A et al. (2011) Quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta for studies of abdominal aortic aneurysms and related arterial diseases. J Ultrasound Med 30:773-84
Yamamoto, Suguru; Yancey, Patricia G; Zuo, Yiqin et al. (2011) Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. Arterioscler Thromb Vasc Biol 31:2856-64
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

Showing the most recent 10 out of 52 publications