Tykhomyrov A. Proteins of plasminogen/plasmin system as regulators of cell processes and markers of various pathological conditions

he thesis is devoted to establishing a role of proteins of plasminogen/plasmin system in the regulation of activity of platelets and cancer cells and evaluating significance of plasminogen fragments (angiostatins) as markers of various diseases. A comprehensive study of the modulating effect of Lys-plasminogen on aggregative activity and angiogenic function of platelets was carried out. It was shown for the first time that the antiaggregative effects of the Lys form of plasminogen are mediated by the disturbance of agonist-induced reconstruction of the actin cytoskeleton of platelets and inhibition of the release of their alpha-granules. Lys-plasminogen restricts the angiogenic function of platelets by inhibiting the release of endothelial cell growth factor (VEGF) and the formation of angiostatins on the plasma membrane, which are powerful inhibitors of neovascularization. For the first time, the dependence of the de novo formation of angiostatins from the functional state of cells was established. The role of actin, which is exposed on the surface of activated platelets, in the binding of plasminogen and the generation of angiostatins has been uncovered. The scientific view on the involvement of plasminogen/plasmin system proteins in the regulation of thrombus formation, angiogenesis and reparative processes, which is carried out through modulation of the functional state of platelets, has been experimentally substantiated. The mechanisms of regulation of processes associated with malignancy of tumor cells by plasmogen/plasmin have been investigated. It was established for the first time that one of the mechanisms of acquisition of resistance to plasmin-induced apoptosis/anoikis and support of migration activity in A549 lung adenocarcinoma cells are activation of autophagy and induction of the synthesis of the regulatory enzyme TIGAR (TP53-induced glycolysis and apoptosis regulator). It was shown that the ability of 4T1 breast adenocarcinoma cells to produce angiostatins and matrix metalloproteinases negatively correlates with their invasive activity. It was found that angiostatins are the negative regulators of inflammatory processes and malignancy of hyperplastic tissues of the myometrium and mammary gland during the development of benign neoplasms. It has been shown that a decrease in the content of angiostatins in the retina of rats with experimental hyperglycemia may serve as a possible factor in the development of diabetic retinopathy. For the first time, the leading role of astroglial cells in the formation of angiostatins in the nervous tissue has been proven. It has been demonstrated that high levels of angiostatins and active matrix proteinases in the tissues of trophic and ischemic ulcers inhibit reparative processes and play a crucial role in wound chronicity. It has been established that the content of angiostatins in blood serum can be utilized as a marker of the development of cardiovascular diseases and an indicator of their pharmacotherapy efficacy.