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Obscure Enzyme May Play Major Role In Heart Disease

NEW YORK, N.Y. and HAIFA, Israel, April 14, 1998 -- A little-known enzyme may play a significant role in preventing heart attack. A paper appearing April 15 in the prestigious Journal of Clinical Investigation, reports that paraoxonase, an enzyme present in the blood, prevents the oxidation of low-density lipoprotein or LDL, the "bad cholesterol" that is deposited in blood vessels and leads to coronary heart disease. The paper is by Professor Michael Aviram, a biochemist, head of the Lipid Research Laboratory, Faculty of Medicine at the Technion-Israel Institute of Technology and at Rambam Medical Center in Haifa, Israel.

"Paraoxonase is located in the blood on the HDL, the 'good' cholesterol, and it can break down oxidized LDL to non-harmful products," explains Aviram, adding that the discovery of this enzyme's activity opens a possible new route to prevention of heart diseases.

The real function of the enzyme has been something of a mystery since it was discovered more than 40 years ago. Its previously known function was to break down organophosphates, chemicals that are used as insecticides and poison gases. That activity was obviously not the complete story of paraoxonase, as humans do not normally contain these substances in their blood, Aviram realized.

Since the major focus of his past research has been the study of the mechanisms by which oxidized cholesterol and other oxidized lipids accumulate in arterial wall cells, leading to blockage of arteries and formation of atherosclerotic lesions, he decided to study the effect of the enzyme on oxidized lipids. Researchers had previously found a very strong inverse relationship between the activity of paraoxonase in the blood and the risk of heart disease. Lower activity is associated with higher risk. The present study helps us understand the mechanism behind that relationship.

In experiments with a strain of mice that are vulnerable to atherosclerosis, an inverse relationship between cholesterol oxidation and paraoxonase activity was shown. In addition, an increase in the size of the atherosclerotic lesions in the blood vessels of these mice was found to be related to the reduction in paraoxonase activity.

The next step, Aviram said, is "to find out how to regulate the activity of paraoxonase and to increase its level in human blood. If we can find means of changingt the enzyme activity, we can look for methods of intervention. This could have very strong implications for heart disease therapy."

Aviram has worked for the past decade on the mechanism by which blood cholesterol quantity (cholesterol levels), as well as blood cholesterol quality (cholesterol oxidation) affects atherosclerosis. He has shown that patients with a high risk of coronary heart disease have increased LDL oxidation. He has also shown that mice and humans given dietary antioxidants, such as red wine or licorice polyphenols, have reduced oxidation of their LDL and, in parallel in the mice, reduced atherosclerotic lesion size was demonstrated.

"But dietary antioxidants may not be enough," Dr. Aviram says. "Under certain conditions, the oxidative stress in the body is so great that it outpaces the activity of the antioxidants. Thus, the combination of preventing LDL oxidation by antioxidants with the breakdown of oxidized lipids by paraoxonase, may be important in reducing oxidative stress and the resulting atherosclerosis."

The research reported by Aviram was done at the Technion-Israel Institute of Technology and at the University of Michigan Medical School, where he is a visiting professor working with Dr. Bert N. La Du, a leading authority on paraoxonase.

The Technion-Israel Institute of Technology is the country's premier scientific and technological center for applied research and education. It commands a worldwide reputation for its pioneering work in communications, electronics, computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine, among others. The majority of Israel's engineers are Technion graduates, as are most of the founders and managers of its high-tech industries. The university's 11,000 students and 700 faculty study and work in the Technion's 19 faculties and 30 research centers and institutes in Haifa.

The American Technion Society (ATS) is the university's support organization in the United States. Based in New York City, it is the leading American organization supporting higher education in Israel. The ATS has raised $650 million since its inception in 1940, half of that during the last six years. Technion societies are located in 24 countries around the world.

American Society for Technion - Israel Institute of Technology.

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