The importance of apolipoprotein (apo) E level and function in protection against vascular diseases has clearly been established. However, most of the research on the role of apoE has focused on its role in cholesterol metabolism. In view of observations that apoE gene polymorphism also impact on the potential for restenosis after percutaneous transluminal coronary angioplasty, a process in which cholesterol deposition is a late event, we hypothesize that apoE may also confer protection against neointimal formation and arterial hyperplasia by mechanisms independent of its role in cholesterol and lipoprotein transport. The overall goal of this research project is to provide insights into additional mechanisms by which apoE confers protection against vascular disease. Based on strong Preliminary Results obtained in in vitro experiments, we hypothesize that apoE has cytostatic functions in vivo and that apoE attenuates vascular occlusive diseases after arterial injury. We postulate that this protective effect is mediated through signal transduction mechanisms subsequent to apoE interaction with one or more members of the LDL receptor gene family on smooth muscle cells.
Specific Aim 1 will use apoE transgenic and knockout mice to test the hypothesis that apoE has cytostatic function in the arterial wall and protects against injury-induced lesion development by inhibiting proliferation and migration of vascular smooth muscle cells.
Specific Aim 2 will use both in vitro cell culture experiments and in vivo studies with apoE transgenic mice to examine the effectiveness of various apoE isoforms in protecting against neointimal formation and arterial hyperplasia in response to injury.
Specific Aim 3 is designed to explore mechanisms underlying the cytostatic function of apoE. In vitro studies with vascular smooth muscle cells in culture will be used to test the hypothesis that apoE inhibits the Ras signaling cascade that is essential for growth factor-induced migration and proliferation of vascular smooth muscle cells.
Specific Aim 4 is designed to identify the receptor on smooth muscle cells that is responsible for mediating the cytostatic function of apoE. Initial attention will focus on the possible involvement of LRP or the VLDL receptor in this process. Transgenic mice overexpressing human apoE will be crossbred with receptor associated protein-defective knockout mice to obtain smooth muscle cells and animals for these experiments. Understanding the relationship between apoE function and vascular cell response to injury will help to identify subjects at risk for arterial diseases, especially those at risk for restenosis after balloon angioplasty. The results will also contribute valuable information for future studies aimed at using apoE as gene therapy for treatment of arterial occlusive diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061332-01A1
Application #
2906522
Study Section
Metabolism Study Section (MET)
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Basford, Joshua E; Moore, Zachary W Q; Zhou, Li et al. (2009) Smooth muscle LDL receptor-related protein-1 inactivation reduces vascular reactivity and promotes injury-induced neointima formation. Arterioscler Thromb Vasc Biol 29:1772-8
Hui, David Y (2008) Intimal hyperplasia in murine models. Curr Drug Targets 9:251-60
Ting, Harold J; Stice, James P; Schaff, Ulrich Y et al. (2007) Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-alpha. Circ Res 100:381-90
Moore, Zachary W Q; Hui, David Y (2005) Apolipoprotein E inhibition of vascular hyperplasia and neointima formation requires inducible nitric oxide synthase. J Lipid Res 46:2083-90
Hui, David Y; Basford, Joshua E (2005) Distinct signaling mechanisms for apoE inhibition of cell migration and proliferation. Neurobiol Aging 26:317-23
Pham, Thomas; Kodvawala, Ahmer; Hui, David Y (2005) The receptor binding domain of apolipoprotein E is responsible for its antioxidant activity. Biochemistry 44:7577-82
Moore, Zachary W Q; Zhu, Binghua; Kuhel, David G et al. (2004) Vascular apolipoprotein e expression and recruitment from circulation to modulate smooth muscle cell response to endothelial denudation. Am J Pathol 164:2109-16
Herz, Joachim; Hui, David Y (2004) Lipoprotein receptors in the vascular wall. Curr Opin Lipidol 15:175-81
Hui, David Y (2004) Apolipoprotein E-induced cell signaling in the vessel wall. Rev Endocr Metab Disord 5:335-41
Zhu, Yanjuan; Hui, David Y (2003) Apolipoprotein E binding to low density lipoprotein receptor-related protein-1 inhibits cell migration via activation of cAMP-dependent protein kinase A. J Biol Chem 278:36257-63

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