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Developing treatments that lower blood cholesterol levels

Institution: Scripps Research Institute
Investigator(s): Linda Curtiss, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0034 Award: $746,536
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Atherosclerosis is a disease that blocks blood flow in all the vessels in the body. When this occurs in the heart, it leads to a heart attack. High levels of cholesterol in the blood increase everyone's risk for the development of this disease. People who smoke have higher levels of cholesterol in their blood and a significantly higher risk for the development of atherosclerosis and heart attacks. Cholesterol is transported in the blood in large cholesterol-rich particles called lipoproteins. These lipoproteins contain a protein called apoE. The liver is the only organ in the body that can break down cholesterol and remove it from the body. ApoE protein is essential to get cholesterol out of the blood and to the liver. Normal laboratory animals have apoE protein in their blood and do not get atherosclerosis. We have experimental animals (called apoE-deficient mice) who have no apoE in their blood. These mice have high cholesterol levels and develop severe atherosclerosis. Other researchers have shown that a single injection of apoE protein into animals can reduce blood cholesterol. Our laboratory has designed a smaller synthetic form of the apoE protein called a synthetic apoE peptide. When this synthetic apoE peptide is injected into the hypercholesterolemic apoE-deficient mice, transport of cholesterol to the liver is increased and cholesterol in the blood is decreased. It is now important to determine if repeated administration of this synthetic apoE peptide into laboratory animals can maintain the lowered levels of cholesterol and thus reduce atherosclerosis. This project will also identify the characteristics of the synthetic apoE peptide that enable it to lower cholesterol so that a safe and effective drug can be designed for use in people with high cholesterol. It is important for tobacco users to quit so that the cholesterol in their blood is reduced, but not everyone will be able to quit. Furthermore, some may have existing atherosclerotic disease from previous long term use of tobacco. Studies of the synthetic apoE peptide could lead to the development of a safe and effective drug for lowering cholesterol and thus lower the risk of heart attacks in smokers.

Final Report
All individuals who use tobacco have a marked increased risk of having cardiovascular disease. This disease kills and disables more people in the United States than any other. There is good evidence that cholesterol transported in the lipoproteins contributes directly to the development and progression of atherosclerosis. If the cholesterol in these lipoproteins is lowered, not only is the risk of cardiovascular disease lowered, but also the disease can be reversed.

The goal of this proposal is to test in vivo the effectiveness of synthetic peptides, to bind lipoprotein receptors in the liver and facilitate specific lowering of plasma cholesterol. We have tested this hypothesis in C57BL/6J apoE-deficient and LDL-R-deficient mice. The early development of lesions in these mice makes them a superb in vivo model for studies of the pharmacologic treatment of severe hyperlipidemia. We have observed that the clearance of cholesterol-rich atherogenic lipoproteins are increased by injection of a peptide mimic. This peptide targets specifically to these cholesterol-rich lipoproteins and directs their hepatic uptake. The outcome of increased hepatic clearance of the apoE peptide-bound, cholesterol-rich particles is a decrease in circulating atherogenic lipoproteins. The predicted consequences of this peptide-facilitated clearance will be a lowered plasma cholesterol, a decrease in lesion development and perhaps even reversal of existing disease.
Publications

A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophage in atherosclerotic lesions of LDL-receptor-dificient mice
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA ART
Yr: 1998 Vol: 101 Nbr: Abs: Pg: 353-363

A minimally lipidated form of cell-derived apo E exhibits isoform-specific stimulation of neurite outgrowth in the absence of exogenous lipids or lipoproteins
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: DeMattos RB, Curtiss LK, Williams DL ART
Yr: 1998 Vol: 273 Nbr: Abs: Pg: 4206-4212

Chemokines and atherosclerosis
Periodical: Current Opinion in Lipidology Index Medicus:
Authors: Terkeltaub R, Boisvert WA, Curtiss LK ART
Yr: 1998 Vol: 9 Nbr: Abs: Pg: 397-405

An apolipoprotein E synthetic peptide selectively modulates the transcription of the gene for rat ovarian theca and interstitial cell P450 17 alpha-hydroxylase, C17-20 lyase
Periodical: Journal of Lipid Research Index Medicus:
Authors: Zhang G, Curtiss LK, Wade RL, Dyer CA ART
Yr: 1998 Vol: 39 Nbr: Abs: Pg: 2406-2414

Radiolabeled MDA2, an oxidation-specific monoclonal antibody identifies native atherosclerotic lesions in vivo
Periodical: Journal of Nuclear Cardiology Index Medicus:
Authors: Tsimikas S, Palinski W, Halpern SE, Yeung DW, Curtiss LK, Witztum JL ART
Yr: 1999 Vol: 6 Nbr: Abs: Pg: 41-53

IL-8 and its receptor CXCR2 in atherosclerosis
Periodical: Immunologic Research Index Medicus:
Authors: Boisvert WA, Curtiss LK, Terkeltaub RA ART
Yr: 2000 Vol: 21 Nbr: Abs: Pg: 129-137

Leukocyte CD11b expression is not essential for the development of atherosclerosis in mice
Periodical: Journal of Lipid Research Index Medicus:
Authors: Kubo N, Boisvert WA, Ballantyne CM, Curtiss LK ART
Yr: 2000 Vol: Nbr: Abs: Pg:

Apolipoprotein E and atherosclerosis
Periodical: Current Opinion in Lipidology Index Medicus:
Authors: Curtiss LK, Boisvert WA ART
Yr: 2000 Vol: 11 Nbr: Abs: Pg: 243-251

Apolipoprotein E and atherosclerosis, a protein with multiple hats
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Curtiss LK ART
Yr: 0 Vol: Nbr: Abs: Pg: