Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracellular matrix remodeling occurs during ovarian follicular development, mediated by plasminogen activators (PAs) and PA inhibitors including protease nexin-1 (PN-1). In the present study we measured expression/activity of the PA system in bovine follicles at different stages of development by timed collection of ovaries during the first follicular wave and during the periovulatory period, and in follicles collected from an abattoir. The abundance of mRNA encoding PN-1, tissue-type PA (tPA), urokinase (uPA) and PA inhibitor-1 (PAI-1) were initially upregulated by human chorionic gonadotropin (hCG) in bovine preovulatory follicular wall homogenates. PN-1, PAI-1 and tPA mRNA expression then decreased near the expected time of ovulation, whereas uPA mRNA levels remained high. PN-1 concentration in follicular fluid (FF) decreased and reached the lowest level at the time of ovulation, whereas plasmin activity in FF increased significantly after hCG. Follicles collected from the abattoir were classified as non-atretic, early-atretic or atretic based on FF estradiol and progesterone content: PN-1 protein levels in FF were significantly higher in non-atretic than in atretic follicles, and plasmin activity was correspondingly higher in the atretic follicles. No changes in PN-1 levels in FF were observed during the growth of pre-deviation follicles early in a follicular wave. These results indicate that PN-1 may be involved in the process of atresia in non-ovulatory dominant follicles and the prevention of precocious proteolysis in periovulatory follicles.
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PMID:Expression of protease nexin-1 and plasminogen activators during follicular growth and the periovulatory period in cattle. 1638 16

The thrombolytic serine protease cascade is intricately involved in activation of innate immune responses. The urokinase-type plasminogen activator and receptor form complexes that aid inflammatory cell invasion at sites of arterial injury. Plasminogen activator inhibitor-1 is a mammalian serpin that binds and regulates the urokinase receptor complex. Serp-1, a myxomaviral serpin, also targets the urokinase receptor, displaying profound anti-inflammatory and anti-atherogenic activity in a wide range of animal models. Serp-1 reactive center site mutations, mimicking known mammalian and viral serpins, were constructed in order to define sequences responsible for regulation of inflammation. Thrombosis, inflammation, and plaque growth were assessed after treatment with Serp-1, Serp-1 chimeras, plasminogen activator inhibitor-1, or unrelated viral serpins in plasminogen activator inhibitor or urokinase receptor-deficient mouse aortic transplants. Altering the P1-P1' Arg-Asn sequence compromised Serp-1 protease-inhibitory activity and anti-inflammatory activity in animal models; P1-P1' Ala-Ala mutants were inactive, P1 Met increased remodeling, and P1' Thr increased thrombosis. Substitution of Serp-1 P2-P7 with Ala6 allowed for inhibition of urokinase but lost plasmin inhibition, unexpectedly inducing a diametrically opposed, proinflammatory response with mononuclear cell activation, thrombosis, and aneurysm formation (p < 0.03). Other serpins did not reproduce Serp-1 activity; plasminogen activator inhibitor-1 increased thrombosis (p < 0.0001), and unrelated viral serpin, CrmA, increased inflammation. Deficiency of urokinase receptor in mouse transplants blocked Serp-1 and chimera activity, in some cases increasing inflammation. In summary, 1) Serp-1 anti-inflammatory activity is highly dependent upon the reactive center loop sequence, and 2) plasmin inhibition is central to anti-inflammatory activity.
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PMID:Identification of myxomaviral serpin reactive site loop sequences that regulate innate immune responses. 1640 26

Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen activator (uPA). Although the roles of uPA and PAI-1 in plasmin generation and the degradation of fibrin are well known, recent evidence also suggests that they can participate in acute inflammatory conditions that involve neutrophil activation. In the present experiments, we found that the addition of PAI-1 to LPS- stimulated neutrophils resulted in enhanced nuclear translocation of NF-kappaB and increased production of the proinflammatory cytokines IL-1beta, Tnf-alpha, and Mip-2. uPA and the kringle domain (KD) of uPA potentiated cytokine expression and NF-kappaB activation by neutrophils cultured with LPS, and had additive effects when combined with PAI-1. The c-Jun N-terminal kinase (JNK) was activated after exposure of resting neutrophils to PAI-1 or the uPA KD. Enhanced JNK activation, but not that of other kinases induced by LPS, was present in neutrophils cocultured with PAI-1 or uPA KD. Inhibition of JNK activation prevented the potentiation of expression of proinflammatory cytokines induced by PAI-1 or uPA KD in LPS stimulated neutrophils. These results demonstrate that PAI-1 and uPA KD enhance LPS-induced neutrophil responses through their effects on JNK mediated pathways.
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PMID:Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK-mediated pathway. 1667 75

Astrocytes are thought to be critical to neurons' surviving damage caused by ischemic stroke or other injury. Plasminogen activator inhibitor-1 is one of the active soluble factors released by astrocytes and regulates plasminogen activator-plasmin proteolytic sequence in the CNS as a serpin. In this study, we show that plasminogen activator inhibitor-1 can promote neurite outgrowth and survival of rat pheochromocytoma cells in serum-deprived conditions, and that this neuroprotective activity is correlated with enhanced activation of both extracellular signal-regulated kinases following a direct phosphorylation of nerve growth factor receptor, Trk A, and of c-Jun. Our results suggest that plasminogen activator inhibitor-1 can act as a neurotrophic factor, protecting neurons from serum deprivation-induced neuron death not only by compensating for nerve growth factor functions, but also by activating the c-Jun/activating protein-1 pathway.
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PMID:Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun pathways. 1667 72

Plasminogen (Plg) activator inhibitor-1 (PAI-1) is an important fibrosis-promoting molecule. Whether this effect can be attributed to PAI-1's activity as an inhibitor of plasmin generation is debated. This study was designed to investigate the role of Plg in renal fibrosis using in vivo and in vitro approaches. Plg-deficient (Plg-/-) and wild-type (Plg+/+) C57BL/6 mice were subjected to unilateral ureteral obstruction or sham surgery (n = 8/group; sham, days 3, 7, 14, and 21). Plg deficiency was confirmed by the absence of Plg mRNA, protein, and plasmin activity. After 21 d of unilateral ureteral obstruction, total kidney collagen was significantly reduced by 35% in the Plg-/- mice. Epithelial-to-mesenchymal transition (EMT), as typified by tubular loss of E-cadherin and acquisition of alpha-smooth muscle actin, was also significantly reduced in Plg-/- mice, 76% and 50%, respectively. Attenuation of EMT and fibrosis severity in the Plg-/- mice was associated with significantly lower levels of phosphorylated extracellular signal-regulated kinase (ERK) and active TGF-beta. In vitro, addition of plasmin (20 microg/ml) to cultures of murine tubular epithelial cells initiated ERK phosphorylation within minutes, followed by phenotypic transition to fibroblast-specific protein-1+, alpha-smooth muscle actin+, fibronectin-producing fibroblast-like cells. Both plasmin-induced ERK activation and EMT were significantly blocked in vitro by the protease-activated receptor-1 (PAR-1) silencing RNA; by pepducin, a specific anti-PAR-1 signaling peptide; and by the ERK kinase inhibitor UO126. Plasmin-induced ERK phosphorylation was enhanced in PAR-1-overexpressing tubular cells. These findings support important profibrotic roles for plasmin that include PAR-1-dependent ERK signaling and EMT induction.
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PMID:Plasmin(ogen) promotes renal interstitial fibrosis by promoting epithelial-to-mesenchymal transition: role of plasmin-activated signals. 1726 41

Integrins play a major role in cell adhesion and migration. Previous work reported that a cleaved form of integrin alpha6 (alpha6p) was detected in invasive human prostate cancer tissue, absent in normal prostate tissue and was produced by urokinase-type Plasminogen Activator (uPA) in a plasmin-independent manner. Using site-directed mutagenesis we identified amino acid residues R594 and R595, located in the "stalk" region of integrin alpha6, as essential for cleavage. The cleavage site is located on the extracellular region of the protein between the beta-barrel domain and the thigh domain. Prostate cancer cells (PC3N) were stably transfected to overexpress the cleavable, wild-type (PC3N-alpha6-WT) or the non-cleavable form of integrin alpha6 (PC3N-alpha6-RR). The number of cells invading laminin 111- and laminin 332-coated filters by PC3N-alpha6-WT cells increased by threefold as compared to PC3N-alpha6-RR cells. Plasminogen activator inhibitor-1 (PAI-1) reduced the invasion of PC3N-alpha6-WT cells by approximately 42% through laminin 332-coated filters and plasmin inhibitor aprotinin had no significant effect. Linear cell migration increased production of integrin alpha6p in the PC3N-alpha6-WT cells and not in the PC3N-alpha6-RR cells and 32% of the PC3N-alpha6-WT cells migrated on laminin 111 in the linear migration assay as compared to the 5% PC3N-alpha6-RR cells. These data taken together suggest that the uPA-mediated cell surface cleavage of the alpha6 integrin extracellular domain is involved in tumor cell invasion and migration on laminin.
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PMID:Integrin alpha6 cleavage: a novel modification to modulate cell migration. 1730 20

The plasminogen activator (PA) system, which controls the formation and activity of plasmin, plays a key role in modulating hemostasis, thrombosis, and several other biological processes. While a great deal is known about the function of the PA system, it remains a focus of intensive investigation, and the list of biological pathways and human diseases that are modulated by normal and pathologic function of its components continues to lengthen. Because of remarkable advances in molecular genetics, the laboratory mouse has become the most useful animal system to study the normal and pathologic functions of the PA system. The purpose of this review is to summarize studies that have used genetically modified mice to examine the functions of the PA system in hemostasis and thrombosis, intimal hyperplasia after vascular injury, and atherosclerosis. Particular emphasis is placed on the vascular functions of PA inhibitor-1, a key regulator of the PA system, and the multiple variables that appear to account for the complex role of PA inhibitor-1 in regulating vascular remodeling. Lastly, the strengths and limitations of using mice to model human vascular disease processes are discussed.
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PMID:Vascular functions of the plasminogen activation system. 1737 40

Plasminogen activator inhibitor-1 (PAI-1) increases injury in several liver, lung and kidney disease models. The objective of this investigation was to assess the effect of PAI-1 deficiency on cholestatic liver fibrosis and determine PAI-1 influenced fibrogenic mechanisms. We found that PAI-1(-/-) mice had less fibrosis than wild type (WT) mice after bile duct ligation. This change correlated with increased tissue-type plasminogen activator (tPA) activity, and increased matrix metalloproteinase-9 (MMP-9), but not MMP-2 activity. Furthermore, there was increased activation of the tPA substrate hepatocyte growth factor (HGF), a known anti-fibrogenic protein. In contrast, there was no difference in hepatic urokinase plasminogen activator (uPA) or plasmin activities between PAI-1(-/-) and WT mice. There was also no difference in the level of transforming growth factor beta 1 (TGF-beta1), stellate cell activation or collagen production between WT and PAI-1(-/-) animals. In conclusion, PAI-1 deficiency reduces hepatic fibrosis after bile duct obstruction mainly through the activation of tPA and HGF.
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PMID:PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. 1756 Oct

Prolonged physical exercise is associated with multiple changes in blood hemostasis. Eccentric muscle activation induces microtrauma of skeletal muscles, inducing an inflammatory response. Since there is a link between inflammation and coagulation we speculated that downhill running strongly activates the coagulation system. Thirteen volunteers participated in the Tyrolean Speed Marathon (42,195 m downhill race, 795 m vertical distance). Venous blood was collected 3 days (T1) and 3 h (T2) before the run, within 30 min after finishing (T3) and 1 day thereafter (T4). We measured the following key parameters: creatine kinase, myoglobin, thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen, plasminogen-activator-inhibitor-1 antigen and thrombelastography with ROTEM [intrinsic pathway (InTEM) clotting time, clot formation time, maximum clot firmness, alpha angle]. Thrombin generation was evaluated by the Thrombin Dynamic Test and the Technothrombin TGA test. Creatine kinase and myoglobin were elevated at T3 and further increased at T4. Thrombin-antithrombin complex, prothrombin fragment F1 + 2, D-dimer, plasmin-alpha(2)-antiplasmin complexes, tissue-type plasminogen activator antigen and plasminogen-activator-inhibitor-1 antigen were significantly increased at T3. ROTEM analysis exhibited a shortening of InTEM clotting time and clot formation time after the marathon, and an increase in InTEM maximum clot firmness and alpha angle. Changes in TGA were indicative for thrombin generation after the marathon. We demonstrated that a downhill marathon induces an activation of coagulation, as measured by specific parameters for coagulation, ROTEM and thrombin generation assays. These changes were paralleled by an activation of fibrinolysis indicating a preserved hemostatic balance.
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PMID:Blood coagulation activation and fibrinolysis during a downhill marathon run. 1758 17

Hyaluronan or hyaluronic acid (HA) has been used to treat osteoarthritic knees for more than 30 years. Here, we tested the hypothesis that HA with high molecular weight (MW) would have greater effects than HA with low MW on the expression of the plasminogen activator (PA)/plasmin system and gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] during early development of osteoarthritis (OA). We compared the levels of MMP-2, MMP-9, urokinase-type PA (u-PA), and PA inhibitor-1 (PAI-1) in a series of chondral, meniscal, and synovial cultures of early OA after treatment with or without three different MW HA products (Hyalgan and Artz with low MW, and Synvisc with high MW). Gelatin zymography revealed that three different HA products could decrease the secretion of MMP-2 in all tissue cultures and MMP-9 in meniscal and synovial cultures time-dependently. Enzyme-linked immunosorbent assay showed that Artz and Synvisc had significant inhibition on u-PA and PAI-1 levels after 24 h, but Hyalgan did at 96 h. Compared with Hyalgan and Artz, Synvisc provided the greatest ability to inhibit MMP-2, MMP-9, u-PA, and PAI-1 expression. Our studies clearly demonstrate that the therapeutic effects of using HA to treat early OA may be partially dependant on downregulation of the PA/plasmin system and gelatinases expression, which delay the structural progression of the disease. HA with high MW might have a greater ability than that with low MW to offer effective protection for articular cartilage.
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PMID:Effects of different molecular weight hyaluronan products on the expression of urokinase plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis. 1797 44


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