Механізми атерогенензу: основи патогенетичної терапії

Abstract

У статті наведені сучасні уявлення про патогенез атеросклеротичного ураження судин. Зазначені молекулярно-генетичні, імунологічні, клітинні механізми, роль системного запалення, ендотеліальної дисфункції та кооперації патогенних чинників. Вказані основні мішені фармакологічного впливу при атерогенез і. Особлива увага приділена новітнім даним про молекулярні фактори, які запускають процеси запалення, пероксидації, активацію імунокомпетентних клітин, зумовлюють інсулінорезистентність та беруть участь у атерогенезі. Зазначені перспективні напрямки профілактики та лікування атеросклерозу; В статье изложены современные представления о патогенезе атеросклеротического поражения сосудов. Указаны молекулярно-генетические, иммунологические, клеточные механизмы, роль системного воспаления, эндотелиальной дисфункции и кооперации патогенных факторов. Указаны основные мишени фармакологического воздействия при атерогенезе. Особое внимание уделено новейшим данным о молекулярных факторах, запускающих процессы воспаления, пероксидации, активации иммунокомпетентных клеток, формирования инсулинорезистентности и влияющих на атерогенез. Указаны перспективные направления профилактики и лечения атеросклероза; Atherosclerosis of arteries is the morphological basis of many diseases associated with disorders of the vascular blood supply to tissues and organs with chronic or acute ischemia and subsequent metabolic, necrotic and sclerotic effects. Atherosclerosis underlying coronary heart disease, including myocardial infarction, brain-stroke, which are the main causes of death of cardiac and neurological patients. One of the most important components of atherosclerotic vascular wall is cholesterol. Cholesterol synthesized mainly in the hepatic cells by about 100 consecutive reactions involving more than 300 different protein molecules. Cholesterol plays an important function in the body – is part of the biological membranes of all cells and affect their properties, is the source of bile acids, steroid hormones. Among the many theories to explain atherogenesis – namely lipoprotein infiltration, endothelial dysfunction, peroxidation, monoclonal, genetic, hormonal, inflammatory, autoimmune, infectious – none is perfect and does not give an exhaustive answer how to prevent, stop or secure its back development. However, there is a proven part of many inflammatory mediators and reactions involving immune cells in the formation of atherosclerotic plaques, which can be considered as a productive specific inflammation. And it is the use of drugs which act on the inflammatory component of atherogenesis, along with lipid-lowering therapy, and antiplatelet, endothelial protectors are promising therapeutic areas. The article presents the current understanding of the pathogenesis of atherosclerotic vascular disease. There was shown molecular, genetic, immunological, cellular mechanisms, the role of systemic inflammation, endothelial dysfunction and cooperation pathogens. The article identifies the major target for pharmacological intervention in atherogenesis. Particular attention is given to the latest data on the molecular factors that trigger inflammation, peroxidation and activation of immune cells, are responsible for insulin resistance. The important role in atherogenesis played genetic factors. There are numerous variants of genetic mutations, including the most common mutation in the structure of the gene of the receptor of cholesterol, due to which there is no capture of low density lipoproteins by cells, resulting in their accumulation in the blood. The cause of hypercholesterolemia can be hereditary defects apoB-100, its increased synthesis and secretion. This also leads to the accumulation of cholesterol in the blood as part of low density lipoproteins. Insulin, thyroid hormones increase the formation of receptors of low density lipoproteins, so this explains hypercholesterolemia in diabetes mellitus and hypothyroidism. Low density lipoproteins may be subject to chemical modification in terms of improved free radical oxidation in the body and non-enzymatic glycosylation of proteins with an increase in blood glucose. Recognizing of defective proteins and lipids, macrophages phagocytose them and enter the tissue to form xanthoma in the skin, atherosclerotic plaques in artery walls. Molecular mechanisms of atherogenesis are studied in detail to find new targets of pharmacological effects on the atherosclerotic process. Important role in atherogenesis play immunocompetent cells and cytokines, which actively allocated activated and damaged cells. In response to cytokines, macrophages form a large number of matrix metalloproteinases, which are involved in the degradation of collagen, extracellular matrix and destabilization of plaques. Much attention is paid to nuclear transcription factors – activating protein-1 and nuclear factor kappa B (NFkB), and receptors that are activators or inhibitors of these factors and their ligands. Shown, that inhibition of glycosphingolipid synthesis may be a novel approach to ameliorate atherosclerosis and arterial stiffness. Shown promising areas of prevention and treatment of atherosclerosis.