06 July 2017

Can atherosclerosis be reversed?

Anna Stavina, XX2 century

Atherosclerosis is a disease that disrupts the normal blood flow in the arteries and, ultimately, causes heart attacks and strokes. Atherosclerosis is characterized by the appearance of atherosclerotic plaques on the inner surface of the vessels, which are accumulations of "bad" cholesterol. Plaques damage the arteries, which leads to the appearance of blood clots, blood clots that can clog the vessel and disrupt the blood supply to vital organs.

The rate of progression of atherosclerosis depends on both the genetic characteristics of the patient and his diet. At the same time, an important role in the development of atherosclerosis is played by the inflammatory process that occurs at the place of attachment of the plaque to the vessel wall.

"Even the most modern and effective cholesterol-lowering drugs, PCSK9 inhibitors, not to mention widely used statins, are not able to neutralize the damage that atherosclerosis causes to blood vessels over time. These drugs cannot prevent 500 thousand heart attacks occurring in the United States annually, – says the head of the study, Dr. Edward Fisher, director of the Marc and Ruti Bell Vascular Biology and Disease Program (Marc and Ruti Bell Vascular Biology and Disease Program) – We need next-generation drugs, funds that were they would target the immune response caused by accumulated cholesterol in the body, and drugs that can "dissolve" cholesterol plaques."

Settling in the arteries, "bad" cholesterol (more precisely, low-density lipoproteins) provokes an immune response, that is, plaques cause inflammation. Monocytes, cells of the immune system, are directed to the places where cholesterol accumulates and turn into macrophages of two varieties, either "inflammatory" or "healing".

In a picture from the NYU Langone Mechanism press release Shown to Reverse Disease in Arteries monocytes on the cholesterol plaque are highlighted in red – VM.

In the course of a number of previous studies, scientists have managed to show that the "specialization" of monocytes is associated with the progress (or regression) of atherosclerosis. If monocytes turn into M1 type macrophages ("inflammatory"), the disease progresses. These cells stimulate inflammation. Conversely, a decrease in the total number of macrophages in plaques and an increase in the proportion of "healing" macrophages M2 are associated with regression of the disease and a decrease in the size of plaques. Increase in the number of macrophages M2 leads to a decrease in the severity of microtrauma appearing on the walls of blood vessels due to plaques. And this, in turn, reduces the risk of atherosclerotic complications: thrombosis, heart attacks and strokes.

In the course of a new study, scientists have found that "therapeutic" macrophages of type M2 are necessary to reduce atherosclerotic inflammation and "dissolve" plaques. At least, this was demonstrated on experimental mice. For the work, the scientists brought out a special line of mice whose monocytes were not capable of migrating into plaques. These mice were fed fatty foods that mimicked the standard "Western diet", which led to an increase in cholesterol levels and the development of atherosclerosis. The researchers then transplanted the atherosclerosis-affected mouse aorta into normal healthy mice. Thus, the blood vessel with plaques turned out to be filled with blood with a normal cholesterol content. This immediately led to an increase in the number of M2 macrophages in the plaques and the regression of the latter. If the aorta was attached to mice from the line derived for the experiment, then there was no improvement in the condition of the vessel. Similar results were obtained in experiments without the use of surgical methods.

If we talk about the clinical application of the results of the new work, it is not yet clear how to make monocytes turn into "useful" macrophages. It is unclear, in particular, whether lowering the patient's cholesterol level by itself can stimulate the appearance of M2-type macrophages. But new imaging techniques may soon provide scientists with a chance to study the quantitative and qualitative composition of the macrophage population in plaques. Soon, if researchers understand how to provoke the production of more M2 macrophages, new therapeutic approaches to the treatment of atherosclerosis may appear. According to Dr. Fischer, it is important that these approaches work at the stage when the disease has not yet led to the appearance of blood clots – upon reaching this point, the violations become irreversible.

Currently, the authors of a new study are trying to detect local signaling pathways that "tell" monocytes that they need to turn into M2-type macrophages. Among the possible candidates for the role of a conductor of this information are interleukin-4 and interleukin-13. Previous studies have shown that these compounds are associated with the maturation of M2 macrophages. They trigger the STAT6 signaling pathway, which sends the protein to the nucleus. In the nucleus, the protein triggers genes that cause the monocyte to turn into a macrophage of type M2. A new study has confirmed that blocking this signaling pathway leads to a decrease in the number of M2 macrophages in shrinking plaques.

Now a group of researchers led by Dr. Fischer is experimenting with nanoparticles created on the basis of "good" cholesterol, known for its ability to transport "bad" cholesterol from plaques to the liver for further decomposition. One of the variants of nanoparticles will also deliver interleukin-4 to the plaques. The next step will be to test nanoparticles on pigs, and then, if everything goes well, it will be the turn of human studies.

Portal "Eternal youth" http://vechnayamolodost.ru  06.07.2017

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