[Fibrinolytics: from the thrombolysis to the processes of blood vessels growth and remodeling, neurogenesis, carcinogenesis and fibrosis].

One of the most outstanding scientific achievements in the thrombolysis is the development and administration of fibrinolysin - the first Soviet drug that lyses blood clots. Intracoronary administration of fibrinolysin reduced the mortality of patients with myocardial infarction by almost 20%. For his work in this field Yevgeny Chazov was awarded the Lenin Prize in 1982. Over the next decades, under his leadership, the Cardiology Center established scientific and clinical laboratories that created new generations of drugs based on fibrinolytics for treating patients with myocardial infarction, restoration of blood flow in ischemic tissue, and also studying the mechanisms of remodeling of blood vessels involving the fibrinolysis system. It have been found new mechanisms of regulation of the navigation of blood vessels and nerves growth, tumor growth and its metastasis with the participation of the fibrinolysis system proteins. The review reports the role of the fibrinolysis system in the thrombolysis, blood vessels growth and remodeling, neurogenesis, carcinogenesis and fibrosis. The article is dedicated to the 90th anniversary of academician E.I. Chazov.

[RNA editing. The classical cases and the outlook of new technologies].

This article provides an overview of studied RNA editing cases and the examples of RNA editing investigations that apply to different experimental data. Typical RNA editing site prediction errors and the methods to minimize them are shown. The outlook of up-to-date technologies and further RNA editing studies are discussed.

Multifaced Roles of the Urokinase System in the Regulation of Stem Cell Niches.

Proliferation, subsequent migration to the damaged area, differentiation into appropriate cell types, and/or secretion of biologically active molecules and extracellular vesicles are important processes that underlie the involvement of stem/progenitor cells in the repair and regeneration of tissues and organs. All these functions are regulated through the interaction between stem cells and the microenvironment in the tissue cell niches that control these processes through direct cell-cell interactions, production of the extracellular matrix, release of extracellular vesicles, and secretion of growth factors, cytokines, chemokines, and proteases. One of the most important proteolytic systems involved in the regulation of cell migration and proliferation is the urokinase system represented by the urokinase plasminogen activator (uPA, urokinase), its receptor (uPAR), and inhibitors. This review addresses the issues of urokinase system involvement in the regulation of stem cell niches in various tissues and analyzes the possible effects of this system on the signaling pathways responsible for the proliferation, programmed cell death, phenotype modulation, and migration properties of stem cells.

[PARTICIPATION OF UROKINASE RECEPTOR AND ITS ENDOGENOUS LIGANDS IN BRAIN DEVELOPMENT AND FORMATION OF COGNITIVE FUNCTIONS].

Recently it has been found that the urokinase receptor (uPAR) and its ligands - urokinase (uPA) and SRPX2 protein play an important role in the development and functioning of the brain. There is a strong association between uPAR gene polymorphism and autism disorders in humans. Patients with autism, intractable lobe epilepsy, verbal dyspraxia and perisylvian polymicrogyria display significant changes in uPAR expression. Mice, lacking the uPAR gene develop epilepsy and demonstrate abnormal social behavior. uPA and SRPX2 protein, have been shown to be involved in pathological brain conditions such as autism, cognitive deficits and language disorders. Urokinase system that stimulates blood vessel growth as demonstrated before, also plays an important role in the regulation of the nerve growth via matrix remodeling and activation of neurotrophic and angiogenic factors. Moreover, the urokinase system also functions as a guidance system which determines the growth trajectory of the vessels' and nerves' in tissue regeneration. This review summarizes and integrates the results and recent progress in the field of uPAR and its endogenous ligands in brain development and cognitive functions.

Urokinase plasminogen activator enhances neointima growth and reduces lumen size in injured carotid arteries.

OBJECTIVES: Increases in urokinase plasminogen activator (uPA) have been reported in tissues undergoing remodelling, but its effects on the vessel intima formation are not known. We investigated its effects on carotid artery intima, media and lumen size, as well as smooth muscle cell (SMC) proliferation and migration in vivo. DESIGN AND METHODS: Carotid arteries of rats were distended with an inflated balloon catheter and uPA, or uPA-neutralizing antibodies were applied perivascularly in pluronic gel; control rats received vehicle. Carotid artery structure, cell migration and proliferation were assessed after 4 days by quantitative morphometry and immunohistochemistry. RESULTS: Four days after increasing vessel uPA, the intima/media ratio was double compared to that in control rats (both P < 0.05). The size of the lumen reduced by 75%, compared to the vehicle-treated vessels (P < 0.05). The elevation in uPA also increased SMC numbers in the intima and media, compared to the vehicle-treated vessels (both P < 0.05). Antibody neutralizing endogenous uPA attenuated the growth responses in the distended arteries, reduced neointimal SMC numbers by approximately 50% and prevented much of the reduction in lumen size. CONCLUSIONS: Thus, local increases in uPA in distended, injured arteries augment SMC migratory and proliferative responses, leading to increases in the thickness of the carotid artery intima and media and a reduction in lumen size; effects at least partially attributable to its proteolytic properties.

[Involvement of urokinase and its receptor in the remodeling of normal and pathological tissue]. / Urokinaza i ee retseptor kak uchastniki strukturnoi perestroiki tkanei v norme i pri patologii.

Urokinase is the main component of the fibrinolytic system and comprises two functions. Namely, the catalytic domain enables to trigger the proteolytic cascade in blood and in the vessel wall, stimulating the activation of growth factors, matrix remodelling and smooth muscle cell proliferation. On the other hand, the amino terminal domain of urokinase that is homologous to epidermal growth factor promotes urokinase to bind to the specific receptor. The cell surface binding of uPA may initiate the activation of the second messengers, protein phosphorylation and cell migration. This dual function of urokinase affects vascular growth, as well as the intimal thickening of the vessel wall after intravascular injury. Also uPA and its receptor are implicated in many physiological and pathological processes, including ovulation, embryogenesis, cancer metastasis, inflammation, and wound healing.

[Effect of growth factors (BFGF and PDGF) on urokinase secretion by smooth muscle cells]. / Vliianie faktorov rosta (bFGF i PDGF) na sekretsiiu urokinazy gladkomyshechnymi kletkami.

The dependence of urokinase (uPA) secretion on basic fibroblast growth factor (bFGF) and platelet-deprived growth factor (PDGF BB) was investigated by using of cultured rat aortic smooth muscle cells (SMC). Growth factors stimulated secretion of urokinase with two-phase kinetics within 1-60 minutes. Namely, "apparent" concentration of uPA in the conditioned media rised to 12.5 nM within the first 1-2 min and 5.8 nM after 30 min of cell stimulation by growth factors, and decreased to basal level at 5 min after stimulation of the cells. The character of uPA-secretion kinetics was similar in response to both growth factors, but the level of secreted uPA was higher in case of PDGF BB. We have shown that this decrease of uPA content in conditioned media is not related to the binding of uPA to the cell surface receptors or extracellular matrix proteins. One can suppose that urokinase secreted within 5 minutes could bind to secretory protein which nature has to be identified. But it was established that this secretory protein, complexing urokinase in cultured media, is not identical to the plasminogen activator inhibitor type 1 (PAI-1).

[Effect of physical load deficiency on the system of calcium transport in the sarcoplasmic reticulum of skeletal muscles amd myocardium]. / Vliianie fizicheskikh nagruzok na sistemu transporta kaltsiia v sarkoplazmaticheskom retikulume skeletnykh myshts i miokarda.

The authors have obtained data characterizing the changes in Ca-transporting function of sarcoplasmatic reticulum (SR) of the skeletal muscles varying in type of muscle fibers as well as the cardiac muscle of the rats during their suspension at an angle of inclination of the upper end of the body of 30 degrees and with the gravity load relief of the hind limbs. Making wide use of the available literature data on the role of Ca2+ as a secondary mediator of cellular homeostasis the authors discuss the possible mechanisms of changing the function of Ca-transporting system of the reticulum directed, by this means, the way of further studies of the transport function of Ca-ATP-ase of the membranes of SR while investigating the effects of weightlessness.

[Regulation of growth and remodeling of blood vessels: the unique role of urokinase].

Urokinase-plasminogen activator (uPA) is a multifunctional fibrinolytic protein activating growth factors, inducing proteolytic cascades, modulating cytokines, regulating receptor shedding, cellular phenotypic modulation and protein expression. These mechanisms underlie the ability of uPA to stimulate the key processes of vascular remodelling, atherosclerosis progression, restenosis and angiogenesis, -- cell migration and proliferation. We summarized data received by us and others concerning the role of uPA in blood vessel remodelling and growth. At the present stage, the uPA may be considered as a perspective target for influences directed on both the prevention of negative arterial remodelling and restenosis as well as the stimulation of vessel growth at ischemic diseases.

Interaction between kringle and growth-factor-like domains in the urokinase molecule: possible role in stimulation of chemotaxis.

The results presented in this paper suggest the presence of an interaction between the kringle- and the growth-factor-like urokinase domains. This interaction regulates chemotactic properties of urokinase. We also show that interaction of urokinase with its "classical" receptor (uPAR) has a "permissive" effect on the interactions between the kringle domain and other targets on the cell surface. On the basis of our data we can suggest that uPAR serves as an "adaptor" for urokinase, and the binding of urokinase kringle domain to its receptor causes immediate activation of intracellular signaling and induction of cell migration.

Urokinase as a multidomain protein and polyfunctional cell regulator.

The urokinase type plasminogen activator (urokinase) plays a pivotal role in the regulation of cell adhesion and migration during tissue remodeling. Urokinase not only specifically cleaves plasminogen and converts it into plasmin but also activates intracellular signaling upon binding to certain receptors on the cell surface. The polyfunctional properties of this protein are associated with its three-domain structure as follows: the C-terminal proteolytic domain containing the serine protease active center, the central kringle domain, and the N-terminal domain homologous to epidermal growth factor. This review considers functional properties of urokinase and of its fragments generated on the cell surface as a result of proteolytic processing. This review will discuss the mechanisms of urokinase-mediated regulation of cellular function upon binding to membrane receptors.

[The role of "growth" domain of urokinase in migration of smooth muscle cells]. / Rol' "rostovogo" domena urokinazy v migratsii gladkomyshechnykch kletok.

The recombinant urokinase plasmogen activator (r-uPA) activated migration of the smooth muscle cells whereas the uPA mutant containing an altered growth factor-like domain (GFD) was ineffective. The uPA seems to possess properties of the urokinase receptor antagonist.

[Ca2+ transport by the skeletal muscle sarcoplasmic reticulum in rats after suspension of the hindlimbs]. / Transport Ca2+ sarkoplazmaticheskim retikulumom skeletnykh myshts krys pri vesovoi razgruzke zadnikh konechnostei.

The functional capacity of skeletal muscle SR was examined in the lateral gastrocnemius (LG) of rats submitted to 1-40-day of disuse produced by a hindlimb suspension (HS). The Ca uptake by SR was measured in homogenate of muscle by means fo Ca-selective electrode, and the time course of SR Ca(2+)-pump inactivation in tissue homogenates incubated at 45 degrees C was studied. There were po significant effects of hindlimb unweighting on muscular Ca pump during 1-14 days of HS. The amount of Ca uptake in SR of LG was about 41% higher in the HS group than in the control after 25 days of HS. After 40 days of HS, the activity of Ca(2+) transport increased by 58% in SR atrophied HS muscle compared with the control. The increased resistance of LG muscle SR Ca pump to thermal exposure was observed after HS. The possible reasons of muscular Ca-pump activation after HS were discussed.

[Urokinase induces adhesion of monocytes to fibrinogen]. / Urokinaza vyzyvaet adgeziiu monotsitarnykh kletok na fibrinogene.

Urokinase activates adhesion of monocytic U937 cells to fibrinogen-coated surface. This effect is due to urokinase proteolytic activity and does not depend on the urokinase binding to its receptor.

Chemotactic effect of urokinase plasminogen activator: a major role for mechanisms independent of its proteolytic or growth factor domains.

Urokinase type plasminogen activator (uPA) converts plasminogen to plasmin and is highly chemotactic for many cell types. We examined, using recombinant wild type and mutated forms of uPA, the extent to which its proteolytic properties, its growth-like domain (GFD) and/or interactions with the specific receptor (uPAR) contribute to the chemotactic activity towards vascular smooth muscle cells (SMC). Recombinant wild type uPA (r-uPA) stimulated cell migration nearly 5.8-fold, inactive r-uPA, with a mutation in the catalitic domain (r-uPA(H/Q)), 3-fold, uPA without growth factor like domain (r-uPA(GFD )), 2.6-fold, and a form containing both mutations (r-uPA(H/Q, GFD ), 3.3-fold. All recombinant forms of uPA, wild type and those with mutations were equally and highly effective (IC50 approximately 20 nM) in displacing 125I-r-uPA bound to SMC. These results indicate that additional mechanisms, not dependent on uPA's proteolytic activity or the binding ability of its GFD to uPAR, are the major contributors to its chemotactic action on SMC.

[Plasminogen activator of urokinase-type: mechanisms of involvement in vessel remodeling and angiogenesis, gene therapy approaches to ischemia]. / Urokinaznyi aktivator plazminogena: mekhanizmy uchastiia v remodelirovanii sosudov i angiogeneze, genno-terapevticheskie podkhody k revaskuliariztsii.

The review summarizes data obtained by the authors and other laboratories concerning the role of urokinase plasminogen activator in vessel remodeling and angiogenesis. The data have shown that urokinase is involved in unfavorable vascular remodeling during the development of restenosis, atherosclerosis and also in the regulation of angiogenesis. Urokinase is a promising target for therapeutic interventions aimed at restenosis prevention. Urokinase gene therapy may be a perspective strategy for the treatment of tissue ischemia.