Atherosclerosis: another target for preventive drugs
A new look at the development of atherosclerosis
S.Kholin, Scientific.ruCardiovascular diseases continue to be the main cause of death of people on the planet.
In about half of the patients, they appear as a result of the action of traditional risk factors on the body, such as chronic stress, reduced physical activity, excessive calorie intake of food, alcohol and tobacco products, etc. However, recent studies of the human genome have found that a significant proportion of patients have a hereditary predisposition to coronary insufficiency and a number of other cardiovascular diseases. Such pathological processes are associated with special gene regions, for example, with the chromosomal region 9p21, which is responsible for the occurrence of certain myocardial diseases, aortic aneurysms in the abdominal cavity, specific lesions of peripheral arteries, etc.
Often, cardiovascular pathology is provoked by atherosclerosis. This chronic artery disease occurs due to a violation of lipid metabolism; it usually begins to form after exposure to the walls of the arteries of such damaging factors as arterial hypertension, stress, chronic inflammatory processes, blood clotting disorders, the influence of viruses and toxins (in particular, nicotine). If, at the same time, the concentration of cholesterol in the patient's blood is increased (or rather, low-density lipoproteins transporting cholesterol through the circulatory system), then its intensive introduction into the vascular wall begins. A cholesterol plaque is gradually formed, to which blood cells phagocytes rush, triggering an inflammatory reaction that promotes the gradual formation of connective tissue (sclerosis) and calcium deposition (calcinosis). Because of this, the vessel wall thickens, thickens and deforms, its inner diameter decreases sharply, blood clots appear, the blood supply to all body systems deteriorates many times. All this initially leads to oxygen starvation (hypoxia) of tissues (primarily the heart muscle, central nervous system, kidneys, etc.), and subsequently causes the appearance of heart attacks, ischemic strokes and other severe complications.
Despite the fact that atherosclerosis has been under the close attention of medical science for a number of decades, many links in the mechanism of its development have not yet been studied. First of all, this concerns the features of the participation of phagocytes in the formation of dense cholesterol masses in the vascular wall (Parks, Lusis, Macrophage Accumulation in Atherosclerosis // N Engl J Med, 2013). Therefore, a group of scientists from the USA and Sweden, led by Yoko Kojima, conducted a complex experimental study to determine the key points of the initial stage of atherosclerosis (Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis // J Clin Invest. 2014). To do this, by influencing the genetic apparatus, laboratory animals were obtained whose cells do not produce CDKN2B (cyclin-dependent kinase inhibitor 2B). The animals were kept on a lipid-rich diet, which provoked characteristic stable biochemical changes in the blood (an increase in the concentration of cholesterol, low-density lipoproteins, triglycerides, etc.). Then, changes in various organs and tissues, structural and functional characteristics of the vascular wall and heart muscle were carefully studied.
As a result of the study, it was found that when the formation of CDKN2B substance by cells (cyclin-dependent kinase inhibitor 2B, cyclin-dependent kinase inhibitor 2B) stops, the rate of accumulation of cholesterol and necrotic (necrotic) masses in the thickness of the artery wall increases many times and plaques and other changes characteristic of atherosclerosis in the vessels are intensively formed. They result from a decrease in the production of a very important protein calreticulin and inhibition of the initial stage of phagocytosis (efferocytosis), which is why phagocytes are unable to clear the vascular wall of cholesterol and dead cells; in addition, special substances (cytokines) appear that stimulate inflammatory changes in the affected areas of the arteries. When CDKN2B synthesis is normalized by cells, the phagocytosis process is activated and atherosclerotic changes in the vessels are not observed.
A diagram from an article in J Clin Invest. – VM
Thus, it is proved that CDKN2B is a key substance in the prevention of atherosclerosis of the arteries. This fact will allow us to develop fundamentally new pharmacological agents for the prevention of cardiovascular pathology.
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