Tissue factor (TF) is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity. TF is needed to produce thrombin from prothrombin. In the extrinsic pathway, TF activates factor Vll. TF is expressed mainly on subendothelial tissues, but TF expression may be induced on endothelial cells by inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha). Subendothelial TF is responsible for initiating fibrin formation at sites of vascular injury, bloodborne TF may be an important contributor to propagation of the developing thrombus. It has been postulated that the blood-borne TF initiates the thrombogenic stimulus, leading to the formation of larger and more stable thrombus. TF may attach to cellular receptors, which in turn affect the production and release of inflammatory mediators. Baseline plasma TF activity has been demonstrated as an independent predictor for cardiovascular death in patients with acute myocardial infarction. TF is expressed by macrophage-derived foam cells in atherosclerotic plaques. TF levels were higher in atheroma from patients with unstable angina than with stable angina. These results suggest that high levels of TF exposed upon plaque rupture trigger atherothrombosis. Inhibition of TF would be expected to reduce thrombosis associated with a variety of diseases. TF pathway is a potential target for new therapeutic agents that can decrease TF activity, such as active site-inactivated factor VIIa, recombinant TF inhibitor and antibodies against TF or peptides interfering with TF-FVIIa complex activity. Significant clinical forms of atherosclerosis, such as sudden death, myocardial infarction, and stroke have common pathogenesis. The occlusion of the vessel lumen is the result from atherosclerotic plaque rupture/erosion that initiate thrombus formation. This thrombus has complex structure and contains predominantly fibrin in addition to platelets, suggesting an important role for the coagulation cascade in plaque thrombus formation. Tissue factor (TF) is known to be the key element in the initiation of the extrinsic pathway of the coagulation cascade and appears to be a critical determinant of atherosclerotic plaque thrombogenicity.

Цель. Выявить молекулярно-генетические предикторы неблагоприятного течения ишемической болезни сердца (ИБС). Материал и методы. Проведено клинико-генетическое обследование 567 больных ИБС, из них за 199 пациентами осуществлено динамическое наблюдение. Генотипы Pro12Pro, Pro12Ala, Ala12Ala гена PPAR-γ2, генотипы L162L и L162V гена PPAR-α, генотипы A603A, A603G, G603G гена тканевого фактора были определены методом полимеразной цепной реакции с последующим рестрикционным анализом. Результаты. Носительство аллеля V162 гена PPAR-α и аллеля Ala12 гена PPAR-γ2 ассоциировано с развитием у больных ИБС таких конечных точек, как возобновление стенокардии, прогрессирование сердечной недостаточности, развитие жизнеугрожающих аритмий, инсульта или транзиторной ишемической атаки, инфаркта миокарда, летальных исходов. Наличие сахарного диабета (СД) 2 типа у больных ИБС ассоциировалось с повышением риска неблагоприятного прогноза в 2,55 раза. Выявлена связь между наличием у больных ИБС СД и смертностью. У больных ИБС, перенесших чрескожное коронарное вмешательство и коронарное шунтирование, комбинированная конечная точка встречалась реже, чем у больных ИБС без оперативных вмешательств на коронарных артериях со снижением риска неблагоприятного прогноза ИБС в 2 раза. Полученные результаты, по-видимому, объясняются пониженной способностью к ингибиции сигнального пути NF-kВ у носителей аллелей V162 и Ala12 генов PPAR-α и PPAR-γ2, что способствует активации факторов иммунного воспаления и атерогенеза с развитием неблагоприятных исходов ИБС. Известно, что СД 2 типа является известным фактором риска ИБС и ее осложнений. Заключение. Наличие СД 2 типа, носительство аллеля V162 гена PPAR-α и аллеля Ala12 гена PPAR-γ2 ассоциировано с неблагоприятными исходами ИБС. У больных ИБС с хирургической реваскуляризацией коронарных артерий снижался риск неблагоприятных исходов ИБС в 2 раза.

Coronary artery disease (CAD) remains the leading cause of death and disability in developed countries. Using traditional risk factors for CAD, it is possible to predict the likelihood of acute coronary events in no more than 50% of cases. Therefore, the study of influence of genetic and epigenetic factors on the development of CAD is extremely important. Research in recent years has shown that vitamin D deficiency is a new risk factor for atherosclerosis and immune inflammation. Vitamin D implements protective effects against immune inflammation through receptors in the vascular wall. A single nucleotide polymorphism of the vitamin D receptor (VDR) gene is a potential risk factor for CAD associated with low vitamin D levels. VDR expression correlates with the expression of pro-inflammatory cytokines and is regulated by microRNAs — microRNA-125a-5p, microRNA-125b-5p, microRNA-214-3p and microRNA-21 These microRNAs regulate the action, synthesis and metabolism of vitamin D and can themselves be influenced by VDR signals through dynamic feedback, which can lead to destabilization of mRNA and inhibition of translation. This literature review highlights the effect of a single nucleotide polymorphism of the VDR gene and microRNA on the pathogenetic mechanisms of CAD.

Purpose The goal of this study is to determine the association of L162V polymorphism of PPAR-alpha gene, A603G polymorphism of tissue factor gene and the risk of coronary heart disease development in Russian population. Materials and Methods A clinical and genetic study of 414 patients with CHD and 220 people of comparable age without CHD which amounted to a control group was performed. L162L and L162V genotypes of L162V polymorphism of PPAR-α gene, A603A, A603G and G603G genotypes of A603G polymorphism of tissue factor gene were determined by polymerase chain reaction followed by restriction analysis. Results A carriage of L162V genotype and V allele of PPAR-α gene was associated with an increase risk of CHD in 2,13 times (L162V genotype) and in 2,21 times (V allele), with an increase in risk of CHD before the age of 45 years in 4,68 times (L162V genotype) and in 3,88 times (V allele). Significantly higher in patients with CHD compared with the general population and in patients with a carriage of G603G genotype and G allele of tissue factor gene was associated with the increase of CHD risk in 2,68 times (G603G genotype) and in 4,37 times (G allele), occurred more frequently in patients with debut of disease at age of 45 years and younger. The level of tissue factor was significantly higher in patients with CHD – carriers G603G genotype compared with carriers A603A genotype (217,9±15,2 pg/ml and 152,6±30,4 pg/ml, respectively, p=0,04). A carriage of the combination of L162V and G603G genotypes was associated with an increased risk of CHD in 3,04 times. Conclusion A carriage of V allele of L162V polymorphism of PPAR-α gene and G allele of A603G polymorphism of tissue factor gene, as well as their pair combination are associated with an increased CHD risk, especially at age 45 years or less.

No abstract

Coronary heart disease still underlies high morbidity and mortality in people of working age. Thus, today one of the most important tasks facing clinical cardiology is the search for new molecular genetic predictors of coronary artery disease associated with the unfavorable course of this disease and the development of complications. In the present review, we analyzed the available data on the mechanisms of vitamin D interrelation with the development of immune inflammation in patients with coronary heart disease. The role of vitamin D and its receptor in cardiovascular diseases and in the development of coronary heart disease, in particular, is considered.Recent studies showed that vitamin D deficiency is a new risk factor for the development of atherosclerosis and immune inflammation. Immune damage of the vascular wall increases the risk of acute coronary syndrome, especially in patients with a predisposition to atherothrombosis. Vitamin D has a multilevel effect on immune inflammation mechanisms by restoring the balance in the system of pro- and anti-inflammatory cytokines. The protective effects of vitamin D on immune inflammation in the vascular wall are realized through vitamin D receptors. The present work re-viewed the studies describing possible mechanisms of immune inflammation regulation by vitamin D and its receptor and activation of immune inflammation in patients with vitamin D deficiency. Further studies of mechanisms of influence of vitamin D receptor on the suppression of immune inflammation are needed.

Peroxisome proliferator receptors alpha (PPAR-α) and their role in atherogenesis has a great practical significance, since there are drugs that can enhance the activity of these receptors. Activation of PPAR-α by fibrates is known to lead to both significant reduction of serum triglyceride levels by activation of lipoprotein lipase, and to the increase of synthesis of the main apolipoproteins within high-density lipoproteins (HDL), contributing to the reverse transport of cholesterol from chylomicrons and very low-density lipoproteins to the liver. Besides, PPAR-α increase the capture of HDL by liver. PPAR-α also participate in the regulation of inflammation, expression of adhesive molecules, production of chemotactic factors, as well as inhibit the proliferation of smooth muscle cells and activity of fibroblasts. These data suggest that PPAR-α are directly involved in the processes of atherogenesis, and their activation may contribute to the regression of atherosclerotic plaque and significant reduction of cardiometabolic risk.

Background. Vitamin D has been shown to reduce the risk of atherosclerosis development. Vitamin D receptors (VDRs) mediate the protective effects of vitamin D on immune inflammation in the vascular wall. Polymorphisms of the VDR gene are involved in the regulation of the stability of its mRNA. The carriage of some polymorphisms may affect the development of atherosclerosis.Objective. To study the availability of vitamin D in patients with coronary artery disease (CAD) with various VDR polymorphisms.Design and methods. The vitamin D level in blood serum was determined by enzyme immunoassay. The genotypes of the VDR gene were determined in 302 patients with CAD and in 196 patients without CAD by PCR.Results. The level of vitamin D in patients with CAD was lower than in controls. The presence of the studied VDR polymorphisms was not associated with an increased risk of CAD. The content of vitamin D was higher in patients with the BB vs. bb genotype of the VDR gene (BsmI), in carriers of the AA vs. aa genotype (ApaI), in carriers of TT vs. tt genotype of the VDR gene (TaqI).Conclusion. TaqI, FokI, ApaI and BsmI polymorphisms are not associated with the risk of CAD. Vitamin D level in the CAD patients with BB and AA genotype of the VDR gene was higher compare with bb and aa genotypes.