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.
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