Will apoE cause regression of atherosclerotic lesions?
Abstracts
Initial Award Abstract |
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Smoking is a well established risk factor for the development of atherosclerosis and heart attack. One characteristic of heart disease is the accumulation of cholesterol within the walls of arteries. Lipid (or fat) loaded macrophages (scavenger cells) in these blood vessels contribute to cell death and the accumulation of extracellular fat and debris, forming raised atherosclerotic lesions on the inner surface of blood vessels. When these lesions rupture, blood clots form, blocking the flow of blood and resulting in oxygen deprivation of heart tissue, death of cardiac cells, and heart attack. High levels of plasma cholesterol are associated with an increased incidence of atherosclerosis, and for those patients with hypercholesterolemia, cholesterol lowering drugs are available. However, many people without elevated plasma cholesterol levels develop atherosclerosis, and therefore drugs that lower cholesterol levels are not beneficial in the majority of cases.
One potential method of treating atherosclerosis is to express a protein in the cholesterol filled cells (macrophages) that helps to remove cholesterol from them and transport it back to the blood where it can be taken up by the liver and excreted from the body. A protein that functions in this way is called apolipoprotein (apo) E. In experimental mice lacking the mouse of the protein, human apoE expression in macrophages greatly reduces the development of atherosclerosis. However, it is not known whether expression of the protein (i.e., overproduction) in the presence of normal levels of the natural protein will provide an additional benefit or if production of this protein in cells will cause atherosclerotic lesions to regress. Here we propose a series of experiments in mice to answer these questions. If apoE can cause atherosclerotic lesions to regress, expression of apoE in the arteries of humans with atherosclerosis may be a beneficial therapeutic approach. |
Final Report |
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Smoking is a well-established risk factor for the development of atherosclerosis and heart attack. One characteristic of heart disease is the accumulation of lipoprotein-derived cholesterol and cholesteryl esters in macrophages of the arterial wall. These lipid-loaded cells contribute to cell death and the accumulation of extracellular fat and debris, forming raised atherosclerotic lesions on the inner surface of blood vessels. When these lesions rupture, blood clots form, blocking the flow of blood and resulting in oxygen deprivation of heart tissue, death of cardiac cells, and heart attack. High levels of plasma cholesterol are associated with an increased incidence of atherosclerosis, and for patients with hypercholesterolemia, cholesterol-lowering drugs are available. However, many people without elevated plasma cholesterol levels develop atherosclerosis, and- therefore drugs that lower cholesterol levels are not beneficial in the majority of cases. One potential method of treating atherosclerosis is to express a protein in the cholesterol-filled cells (macrophages) that helps to remove cholesterol from them and transport it back to the blood where it can be taken up by the liver and excreted from the body. A protein that functions in this way is called apolipoprotein (apo) E. In experimental mice lacking the mouse form of the protein, human apoE expression in macrophages greatly reduces the development of atherosclerosis. However, it is not known whether expression of the protein (i.e., overproduction) in the presence of normal levels of the natural protein will provide an additional benefit or if production of this protein in cells will cause atherosclerotic lesions to regress. If apoE can cause atherosclerotic lesions to regress, expression of apoE in the arteries of humans with atherosclerosis may be a beneficial therapeutic approach.
This study was in effect from July 1, 1998 to January 31, 1999 when it was relinquished to accept an overlapping grant funded by the National Institutes of Health. Considerable progress was made during that time in the generation and breeding of mice with both constituitive and regulated macrophage-specific expression of apoE. These transgenic animals were first (for technical reasons) produced in a strain of mice that are not susceptible to atherosclerosis. They were then bred to a strain of mice that are susceptible to atherosclerosis and that do not express the mouse form of apoE. Atherosclerosis studies are currently underway to determine if macrophage-specific expression of two closely related forms of human apoE differ in -their ability to reduce the development of atherosclerotic lesions. |
