There is a direct relationship between the development of atherosclerosis and the serum levels of native low-density lipoprotein (LDL). Further, there is a long-term ameliorative effect on the arterial vasculature with the lowering of LDL. Both effects are, in part, explained by the actions of LDL on the vascular endothelium. Consequentially, the PI proposes to comprehensively examine the hypothesis that LDL directly perturbs endothelial cells (EC) by modulating these cells to a pro-inflammatory condition. To carry out these investigations, three specific aims have been designed, based on their previous publications and current preliminary data.
Specific Aim I is directed toward examining that portion of LDL that appears to be primarily responsible for EC activation. Studies are targeted toward examination of the interaction of cholesterol with caveolin-1 in caveolae. It is their contention that caveolae are likely affected by cholesterol enrichment. This enrichment appears to initiate intracellular signaling by the activation of kinases, in particular, Ras. This process may occur by the uncoupling of Ras from caveolin- I or by accumulation of Ras in caveolae.
Specific Aim 2 is a logical extension of this process and examines the ensuing specific intracellular signaling. This intracellular signaling pathway distinguishes itself from the traditional pathway, described for activation of EC by cytokines, which initiates transcription through NF-KB. In the case of LDL-induced EC activation, the process occurs via an AP-1 pathway. In conjunction with the detailed examination of this pathway, Specific Aim 3 is designed to fully examine the regulation of ICAM-1, which is directly involved in the pro-inflammatory change of EC. These studies use a novel adenoviral-mediated gene transfer system. This system permits transduction efficiencies approximating 100%, and allows an in-depth study of the regulatory effects of AP-1. Such studies have substantial therapeutic implications since interruption of this signaling pathway should contribute toward halting atherogenesis. This proposal will develop unique fundamental knowledge of the nature of EC activation by LDL, much of which may provide novel rationales for future patient treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL033742-15A1
Application #
6130536
Study Section
Pathology A Study Section (PTHA)
Project Start
1984-07-01
Project End
2004-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
15
Fiscal Year
2000
Total Cost
$331,875
Indirect Cost
Name
University of California Riverside
Department
Type
Schools of Medicine
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92521
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Zeng, Lingfang; Liao, Hailing; Liu, Yi et al. (2004) Sterol-responsive element-binding protein (SREBP) 2 down-regulates ATP-binding cassette transporter A1 in vascular endothelial cells: a novel role of SREBP in regulating cholesterol metabolism. J Biol Chem 279:48801-7
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Wang, Nanping; Verna, Lynne; Chen, Neng-Guin et al. (2002) Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem 277:34176-81
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Pritchard, Kirkwood A; Ackerman, Allan W; Ou, Jingsong et al. (2002) Native low-density lipoprotein induces endothelial nitric oxide synthase dysfunction: role of heat shock protein 90 and caveolin-1. Free Radic Biol Med 33:52-62
Wang, N; Verna, L; Liao Hl et al. (2001) Adenovirus-mediated overexpression of dominant-negative mutant of c-Jun prevents intercellular adhesion molecule-1 induction by LDL: a critical role for activator protein-1 in endothelial activation. Arterioscler Thromb Vasc Biol 21:1414-20
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