Israeli researchers discovered an enzyme that plays a central role in inhibiting atherosclerosis
Merit Sloin
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How is the sclerotic lesion formed in the walls of the arteries, which eventually leads to the clogging of the artery and a heart attack? Given that heart attacks are the number one cause of death in the Western world, this is a question of utmost importance. Cholesterol is a major risk factor in the atherosclerosis process. However, cholesterol is also used in the body to build substances that participate in life processes. It serves as a central component of the cell wall and from it vitamin D, sex hormones and bile acids are formed. About 7% of cholesterol is in the blood, and when the amount of cholesterol in the blood increases, it sinks into the walls of the arteries.
Cholesterol reaches the body from two main sources: from food and self-production, mainly in the liver. When its production is finished, it is packaged in small particles called lipoproteins, which transport it in the bloodstream. Two of them are directly related to atherosclerosis: the LDL ("bad cholesterol") and the HDL ("good cholesterol"). LDL particles carry about two-thirds of the cholesterol in the blood and transport it throughout the body. When their amount increases, they infiltrate the artery wall, where the cholesterol is oxidized. The oxidized cholesterol starts the hardening process, which eventually leads to a heart attack or stroke. The HDL particles carry about a quarter of the amount of cholesterol. They bind excess cholesterol from the artery walls and transport it to the liver. In the liver, cholesterol is turned into bile acids and eliminated from the body.
The body knows how to regulate the level of cholesterol that comes from food. When you eat food rich in cholesterol, less cholesterol from the digestive system is absorbed into the blood, cholesterol production in the liver is inhibited, and more bile acids are formed from it, which are partially eliminated from the body. In old age, these systems begin to lose their efficiency and this is one of the reasons for excess cholesterol in the blood with age.
The levels of LDL and HDL signal the degree of risk of having atherosclerosis. But it turns out that in about 30% of those who have a heart attack, the LDL and HDL levels are normal. The problem with them is that most of the cholesterol in LDL is oxidized (compared to normal conditions and conditions of excess LDL, where only some cholesterol is oxidized).
Oxidized cholesterol, it is believed today, is the main factor in the atherosclerosis process: the process begins when cholesterol-laden LDL particles penetrate the artery wall. In the artery wall, cholesterol is oxidized and the oxidized LDL is engulfed by cells called macrophages. When the oxidized cholesterol accumulates inside the macrophages in large quantities, they turn into "foam cells", which pile on top of each other and form the sclerotic lesion. In the process, inflammatory substances are released from the foam cells that accelerate clotting processes. Eventually the artery becomes blocked by a blood clot that gets stuck on the surface of the sclerotic plaque and clogs the tube cavity. The HDL particles can intervene in the sclerotic process and prevent its progression by binding cholesterol from the sclerotic plaque and transferring it to the liver for removal from the body.
Currently, there is no medication that can fight oxidized cholesterol. On the other hand, high LDL can be lowered with drugs (statins) and low HDL can be raised to a certain extent through physical activity and a daily sip of red wine.
Prof. Michael Aviram, from the Rapoport Institute at the Technion School of Medicine and the Rambam Medical Center in Haifa, began researching oxidized cholesterol about ten years ago. . The body is actually constantly in a state of oxidative stress. To this end, neutralizing substances called antioxidants have been developed, but their action is often insufficient, especially in old age. I thought to myself, that in such a situation we should constantly have heart attacks as a result of the creation of oxidized cholesterol in large quantities. Since this does not usually happen, maybe there is a natural substance in the body that breaks down the oxidized LDL."
In a review of the medical literature on the subject, Aviram found material that piqued his curiosity. "About ten years ago, an article was published about an enzyme called paraoxonase, which indicated a connection between its activity and the chance of developing sclerotic lesions. The higher the activity of the enzyme, the lower the chance of developing sclerotic lesions, and vice versa," says Aviram. "It was also found that paraoxonase does not circulate freely in the blood, but is bound to the HDL particles. So, I thought, it is possible that HDL's ability to break down oxidized cholesterol is related to the fact that paraoxonase is attached to it."
The hypothesis turned out to be correct: Aviram and his team found that paraoxonase associated with HDL breaks down the oxidized LDL in the artery wall. In additional studies it was found that HDL particles to which paraoxonase is attached are capable of breaking down oxidized cholesterol not only in oxidized LDL but also in HDL. "We believe that paraoxonase is the body's second line of defense against the development of the sclerotic lesion," Aviram says. "The first line of defense is manned by the antioxidants, which prevent the production of oxidized cholesterol. If they fail, the paraoxonase attached to HDL enters the picture and breaks down the oxidized cholesterol in the LDL particles. Thus, the 'good cholesterol' actually fights the spread of atherosclerosis."
In the next phase of their research, the researchers tested whether the parocosenase and HDL are able to break down sclerotic lesions that have already formed. When they incubated sclerotic lesions with paraoxonase, and at the same time with HDL particles to which paraoxonase was attached, a 40% decrease in the amount of oxidized LDL in the sclerotic lesions was obtained in both cases. According to Aviram, after such a decrease the development of the sclerotized layer is inhibited to a very large extent. The paraoxonase was able to break down sclerotic lesions in a living system as well, as demonstrated by experiments on transgenic mice carried out by a research team from the University of California in Los Angeles.
In two recent studies, published in the journals "Circulation" and "Vascular Biology" and "Arteriosclerosis Thrombosis", Aviram and his team discovered the mechanism of action of paraoxonase. It turned out that paraoxonase inhibits another enzyme, NADPH oxidase, which is one of the key players in the sclerosis processes. The NADPH oxidase is involved in the oxidation of LDL in the artery wall, and impairing its activity inhibits the creation of oxidative stress and the development of atherosclerosis.
"The findings outline a natural defense mechanism that protects us from atherosclerosis," Aviram says. "We feel that we have opened a new field in the study of the disease, the understanding of which may be able to provide an answer to the leading cause of death in the Western world."
They knew innovations in medicine
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