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Weill Cornell Medical College researchers, led by Dr. Timothy McCaffrey, have discovered a likely molecular cause of atherosclerosis in elevated levels of a gene that makes normal vascular repair go awry. The research, recently published in The Journal of Biological Chemistry, holds the promise of new drug therapies or genetic interventions for preventing or reversing heart disease. It also quite possibly explains the molecular mechanism behind some forms of cancer.

The Use of Human Atherosclerotic Lesions

Dr. McCaffrey's laboratory is one of a select few in the world that utilizes human atherosclerotic lesions to grow cells in culture flasks for functional and genetic analysis. This is made possible by a unique multidisciplinary collaboration of scientists, vascular surgeons, and cardiothoracic surgeons interested in determining the underlying cause and molecular mechanisms of atherosclerosis.

In a series of studies using these patient-derived cells, the McCaffrey group has identified unique growth defects in cells grown from these human lesions, and established their molecular cause as a loss of cell surface receptor. This receptor is required to recognize a "stop" signal to the cells that normally repairs vascular damage. By ignoring this "stop" signal, which is normally conveyed by TGF-ß (transforming growth factor-ß), the cells continue to repair the artery until it is almost closed, thus preventing blood flow.

The Genetic Connection

In further analyzing the cells grown from the lesions by genomic arrays, which can probe thousands of genes simultaneously, the researchers made a significant discovery. They found that the unusual and defective growth properties of the cells were due to activation of a gene called Egr-1, or early growth response gene 1, previously known to be an important part of the human body's vascular repair program.

The present studies demonstrate that Egr-1 has the unexpected effect of being able to suppress the "stop" signal, by blocking the production of the receptor for TGF-ß. Thus, the cells never receive the stop signal and slowly close the artery.

When this type of slow closure occurs in coronary arteries, it causes angina (chest pain), and potentially the slow starvation of the heart muscle that leads to heart failure. When closure of arteries occurs in carotid arteries, which lead to the brain, it can cause strokes and neurodegenerative diseases resulting from insufficient blood supply.

The identification of Egr-1 as a contributing factor in the defective behavior of human cells suggests that new drug therapies or genetic interventions might be useful in preventing or reversing heart disease and some vascular forms of neurodegenerative disease. In effect, scientists would need to design a drug or intervention that would prevent or inhibit the gene Egr-1 from repressing one of the body's major inhibitory mechanisms that restrains vascular repair.

"This intriguing finding could provide significant leads for new lines of therapy that potentially could be useful in the treatment of arteriosclerosis," concludes Dr. David Finkelstein, Pathobiology Program Director at the National Institute of Aging, which partially funded the work.

Surprisingly, many forms of cancer exhibit a similar failure to recognize this same "stop" sign, and so it is possible that this same pathway, or one related to it, may help explain certain aspects of cancer cell behavior.

Atherosclerosis and Aging

Atherosclerosis is the major underlying cause of death in this country, contributing to more than 950,000 deaths per year in the form of heart failure, myocardial infarction, and stroke. In 1997, 450,000 patients underwent balloon angioplasty to dilate narrowed coronary arteries. However, angioplasty and vascular surgeries are complicated by progressive fibroproliferative reclosure (restenosis) of the artery in up to 40 percent of cases within the first six months.

Several well-known risk factors contribute to the development of the atherosclerotic lesion: high cholesterol levels (hyperlipidemia), smoking, and high blood pressure (hypertension). However, such risk factors are relatively small when compared to the risk associated with the normal aging process. The risk of heart disease is directly related to age, such that, by the age of 65, almost half of the surface of the coronary arteries is covered with atherosclerotic lesions.

The Authors

Lead author Dr. Timothy A. McCaffrey is an Associate Research Professor of Cell Biology in the Department of Medicine at Weill Cornell Medical College. He has published extensively on the molecular mechanisms of atherosclerosis.

Other authors contributing to the research include Drs. Baoheng Du, Chenzhong Fu, Craig Kent, Harry Bush, Andrew Schulick, and Karl Krieger of Weill Cornell, and Dr. Tucker Collins of Harvard Medical School.

The research was funded through grants from the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Aging.