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)

The serum lipoprotein(a) [Lp(a)] level is a known risk factor for arteriosclerotic coronary artery disease. However, its association with restenosis after percutaneous transluminal coronary angioplasty (PTCA) is controversial. We hypothesized that the Lp(a) level is a significant risk factor for restenosis after angioplasty through a pathophysiological mechanism leading to excess thrombin generation or inhibition of fibrinolysis. We designed a prospective study of the relation of Lp(a) to outcome after PTCA, in which we measured selected laboratory variables at entry and collected clinical, procedural, lesion-related, and outcome data pertaining to restenosis. Restenosis was defined as >50% stenosis of the target lesion by angiography or as ischemia in the target vessel distribution by radionuclide-perfusion scan. Before the patients underwent PTCA, blood was obtained by venipuncture for measurement of Lp(a), total cholesterol, thrombin-antithrombin (TAT) complex, alpha2-antiplasmin-plasmin (APP) complex, and plasminogen activator inhibitor-1 (PAI-1). Evaluable outcome data were obtained on 162 subjects, who form the basis of this report. Restenosis occurred in 61 subjects (38%). The Lp(a) level was not correlated significantly with TAT, APP, PAI-1, or the TAT-APP ratio. Levels of TAT, APP, and PAI-1 were not statistically different in the patients with versus those without restenosis. The median ratio of TAT to APP was 2-fold higher in the restenosis group, and this difference approached statistical significance (P=0.07). Univariate analysis was performed for the association of clinical, lesion-related, and procedural risk factors with restenosis. Lp(a) levels did not differ significantly in the restenosis versus no-restenosis group, whether assessed categorically (>25 mg/dL versus <25 mg/dL) or as a continuous variable by Mann-Whitney U test. The number of lesions dilated and the lack of family history of premature heart disease were significantly associated with restenosis (P=0.002 and P=0.008, respectively). A history of diabetes mellitus was of borderline significance (P=0.055). By multiple logistic regression analysis, the number of lesions dilated was the only variable significantly associated with restenosis (P=0.03). We conclude that the number of lesions dilated during PTCA is a significant risk factor for restenosis, whereas the serum Lp(a) level was not a significant risk factor for restenosis in our patient population. The TAT to APP ratio merits further study as a possible risk factor for restenosis.
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PMID:Lipoprotein(a) level does not predict restenosis after percutaneous transluminal coronary angioplasty. 971 35

Much attention has been paid to proteinases derived from not only neurons but also microglia in relation to neuronal death. There is accumulating evidence that intra- and extracellular proteinases in these cells are part of the basic machinery of neuronal death pathways. Some members of the ced-3/interleukin-1 beta converting enzyme (ICE) (caspase) family of cysteine proteinases have been thought to play a major role in apoptosis of not only non-neuronal cells but also neurons. Calpain has also been demonstrated to be a mediator of the neurodegenerative response. Recent studies have shown that excitotoxic and ischemic neuronal injury could be attenuated by inhibitors of caspases and calpain. Several recent studies have suggested the involvement of endosomal/lysosomal proteinases, including cathepsins B, D and E, in neuronal death induced by excitotoxins and ischemia. Furthermore, it has been reported that the extracellular tissue-type plasminogen activator/plasmin proteolytic cascade is involved in excitotoxic injury of the hippocampal neurons. In addition to such neuronal proteinases, microglial proteinases are believed to be important for the modification of neuronal functions positively or negatively. Cathepsins E and S derived from microglia have been suggested to contribute to neuronal survival through degradation and removal of beta-amyloid, damaged neurons and cellular debris. On the other hand, 6-hydroxydopamine-induced microglial cell death was inhibited by inhibitors of aspartic proteinases and caspases, suggesting the involvement of cathepsins E and D and caspases in microglial cell death. Therefore, identification of which proteinases play a causative role in neuronal death execution and clarification of the regulators and substrates for such proteinases is very important for understanding the molecular basis of the neuronal death pathways and to develop novel neuroprotective agents.
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PMID:[Involvement of proteinases produced by both neurons and microglia in neuronal lesion and death pathways]. 978 98

In this study, we evaluated the role of proteolytic enzymes belonging to the coagulation, fibrinolytic, and plasma contact systems in the early postoperative phase after orthotopic liver transplantation (OLT). Twenty-nine patients were studied at the time of OLT and during the first 2 postoperative weeks. Blood samples were collected daily after OLT and analyzed for kallikrein-like activity (KK), functional kallikrein inhibition (KKI), plasmin-like activity (PL), and alpha2-antiplasmin (AP). In addition, prekallikrein (PKK), prothrombin (PTH), antithrombin III (AT III), plasminogen (PLG), prothrombin/antithrombin III complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), and plasmin/alpha2-antiplasmin complexes (PAP) were measured. Nineteen patients experienced biopsy-verified acute rejections (AR) and ten patients had uneventful courses and served as controls. Plasma analyses showed that the contact, coagulation, and fibrinolytic systems were activated during OLT. Following OLT, continuous thrombin and plasmin generation was observed, and these effects were more pronounced in the group having an uneventful course than in patients with AR. Factors that could possibly affect plasma proteolytic activity, such as blood product usage during and after OLT and cold ischemia time of the liver graft, did not differ between the groups, nor did the routine liver function tests, alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
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PMID:Plasma proteolytic activity in liver transplant rejection. 1036 91

In focal cerebral ischemia the plasminogen-plasmin system plays a role in the fibrinolysis of vessel-occluding clots and also in the proteolysis of extracellular matrix components, which potentially contributes to brain edema and bleeding complications. The authors investigated the plasminogen activation after middle cerebral artery occlusion with and without reperfusion (reperfusion intervals 9 and 24 hours) in rats by histologic zymography and compared areas of increased plasminogen activation to areas of structural injury, which were detected immunohistochemically. After 3 hours of ischemia, increased plasminogen activation was observed in the ischemic hemisphere. The affected area measured 5.2%+/-8.5% and 19.4%+/-30.1% of the total basal ganglia and cortex area, respectively. Reperfusion for 9 hours after 3 hours of ischemia led to a significant expansion of plasminogen activation in the basal ganglia (68.8%+/-42.2%, P < 0.05) but not in the cortex (43.0%+/-34.6%, P = 0.394). In the basal ganglia, areas of increased plasminogen activation were related to areas of structural injury (r = 0.873, P < 0.001). No such correlation was found in the cortex (r = 0.299, P = 0.228). In this study, increased plasminogen activation was demonstrated early in focal cerebral ischemia. This activation may promote early secondary edema formation and also secondary hemorrhage after ischemic stroke.
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PMID:Plasminogen activation in focal cerebral ischemia and reperfusion. 1069 71

This study was performed to determine whether human urinary soluble thrombomodulin plays a role in liver ischemia-reperfusion injury. Liver ischemia was induced in two groups of dogs. Group 1 was exposed to 60 min ischemia, and group 2 was exposed to 60 min ischemia after preischemic administration of human urinary soluble thrombomodulin. In group 1, the thrombin-antithrombin complex and hyaluronic acid were significantly elevated after ischemia, compared with the preischemic values. While liver issue blood flow and the plasmin-alpha(2)-plasmin inhibitor complex significantly decreased, AST, ALT and m-AST dramatically increased after reperfusion. In group 2, the increase in the thrombin-antithrombin complex and hyaluronic acid was significantly suppressed, and AST, ALT and liver tissue blood flow significantly improved, compared with group 1. Histologically, in group 2, the hepatic tissue structure, including endothelial cells, was relatively intact. These findings suggest that administration of thrombomodulin inhibits endothelial cell injury and coagulopathy and offers protection from liver ischemia-reperfusion injury.
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PMID:Protective effect of human urinary thrombomodulin on ischemia- reperfusion injury in the canine liver. 1081 Feb 13

L-Arginine (Arg) is the substrate for the synthesis of nitric oxide (NO), the endothelium-derived relaxing factor essential for regulating vascular tone and hemodynamics. NO stimulates angiogenesis, but inhibits endothelin-1 release, leukocyte adhesion, platelet aggregation, superoxide generation, the expression of vascular cell adhesion molecules and monocyte chemotactic peptides, and smooth muscle cell proliferation. Arg exerts its vascular actions also through NO-independent effects, including membrane depolarization, syntheses of creatine, proline and polyamines, secretion of insulin, growth hormone, glucagon and prolactin, plasmin generation and fibrinogenolysis, superoxide scavenging and inhibition of leukocyte adhesion to nonendothelial matrix. Compelling evidence shows that enteral or parenteral administration of Arg reverses endothelial dysfunction associated with major cardiovascular risk factors (hypercholesterolemia, smoking, hypertension, diabetes, obesity/insulin resistance and aging) and ameliorates many common cardiovascular disorders (coronary and peripheral arterial disease, ischemia/reperfusion injury, and heart failure). Dietary Arg supplementation may represent a potentially novel nutritional strategy for preventing and treating cardiovascular disease.
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PMID:Arginine nutrition and cardiovascular function. 1105 97

Cardiopulmonary bypass is associated with a systemic inflammatory response, a spectrum of pathophysiologic changes ranging from mild organ dysfunction to multisystem organ failure. Complications include coagulation disorders (bleeding diathesis, hyperfibrinolysis) from platelet defects and plasmin activation, as well as pulmonary dysfunction from neutrophil sequestration and degranulation. Diverse injuries are a consequence of multiple inflammatory mediators (complement, kinins, kallikrein, cytokines). Both plasmin and kallikrein amplify the inflammatory response by activating components of the contact activation system. The full-Hammersmith (high dose) of aprotinin, a serine protease inhibitor approved for reducing blood loss and transfusion requirements in cardiopulmonary bypass, inhibits kallikrein and plasmin, resulting in suppression of multiple systems involved in the inflammatory response. Specifically, inhibition of factor XII, bradykinin, C5a, neutrophil integrin expression, elastase activity, and airway nitric oxide production are observed. Clinical correlates include reduced capillary leak, preserved systemic vascular resistance and blood pressure, and improved myocardial recovery following ischemia. Overall, evidence indicates that aprotinin attenuates the systemic inflammatory response associated with cardiopulmonary bypass.
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PMID:Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. 1123 55

The serine protease tissue-type plasminogen activator (t-PA) initiates the fibrinolytic protease cascade and plays a significant role in motor learning, memory, and neuronal cell death induced by excitotoxin and ischemia. In the fibrinolytic system, the serpin PAI-1 negatively regulates the enzymatic activity of both single-chain and two-chain t-PA (sct-PA and tct-PA). In the central nervous system, neuroserpin (NSP) is a serpin thought to regulate t-PA enzymatic activity. We report that although both sct-PA and tct-PA rapidly form acyl-enzyme complexes with NSP in vitro, the interactions are short-lived, rapidly progressing to complete cleavage of NSP and regeneration of fully active enzyme. All NSP molecules appear to transit through the detectable acyl-enzyme intermediate and progress to completion of cleavage; no subpopulation that functions as a pure substrate was detected. Likewise, all molecules were reactive, with no evidence of a latent subpopulation. The interactions between NSP and t-PA were distinct from those between plasmin and NSP, wherein the same peptide bond was cleaved but there was no evidence of a detectable plasmin-NSP acyl-enzyme complex. The interactions between t-PA and NSP contrast with the formation of long-lived, physiologically irreversible acyl-enzyme complexes between t-PA and PAI-1, suggesting that the physiologic effect of t-PA-NSP interactions may be more complex than previously thought.
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PMID:Acyl-enzyme complexes between tissue-type plasminogen activator and neuroserpin are short-lived in vitro. 1222 52

The serine proteases tissue plasminogen activator, plasmin, and thrombin and their receptors have previously been suggested to contribute to neuronal damage in certain pathological situations. Here we demonstrate that mice lacking protease-activated receptor 1 (PAR1) have a 3.1-fold reduction in infarct volume after transient focal cerebral ischemia. Intracerebroventricular injection of PAR1 antagonist BMS-200261 reduced infarct volume 2.7-fold. There are no detectable differences between PAR1-/- and WT mice in cerebrovascular anatomy, capillary density, or capillary diameter, demonstrating that the neuroprotective phenotype is not likely related to congenital abnormalities in vascular development. We also show that the exogenously applied serine proteases thrombin, plasmin, and tissue plasminogen activator can activate PAR1 signaling in brain tissue. These data together suggest that if blood-derived serine proteases that enter brain tissue in ischemic situations can activate PAR1, this sequence of events may contribute to the harmful effects observed. Furthermore, PAR1 immunoreactivity is present in human brain, suggesting that inhibition of PAR1 may provide a novel potential therapeutic strategy for decreasing neuronal damage associated with ischemia and blood-brain barrier breakdown.
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PMID:The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. 1455 73

Uncontrolled activation of matrix metalloproteinases (MMPs) can result in tissue injury and inflammation, yet little is known about the activation of MMPs during orthotopic liver transplantation (OLT). OLT is associated with increased fibrinolytic activity due to elevated plasmin generation. The serine-protease plasmin not only causes degradation of fibrin clots but is also thought, amongst others, to play a role in the activation of some matrix metalloproteinases. We therefore studied the evolution of MMP-2 and -9 plasma concentrations during OLT and the effect of serine-protease inhibition by aprotinin on the level and activation of these MMPs. In a group of 24 patients who participated in a randomized, double-blind, placebo-controlled study we determined serial MMP-2 and MMP-9 plasma levels during transplantation using ELISA (total MMP), activity assays (activatable MMP) and zymography. In addition, the MMP-inhibitors TIMP-1 and TIMP-2 were assessed by ELISA. The putative regulating factors tumor necrosis factor alpha (TNF-alpha) and tissue-type plasminogen activator (t-PA) were assessed as well. Patients were administered high-dose aprotinin, regular-dose aprotinin or placebo during surgery. Plasma TIMP-1, TIMP-2 and MMP-2 level gradually decreased during transplantation. Approximately two-thirds of total MMP-2 appeared to be in its activatable proMMP form. No release of MMP-2 from the graft could be detected. In contrast, plasma levels of MMP-9 increased sharply during the anhepatic and postreperfusion periods. Peak MMP-9 levels of about eight times above baseline were found at 30 minutes after reperfusion. Most MMP-9 appeared to be in its active/inhibitor-complexed form. No significant differences were observed between the three treatment groups. However, in patients with more severe ischemia/reperfusion (I/R) injury the MMP-9 concentration, particularly of the active/inhibitor-complexed form, remained high at 120 minutes postreperfusion compared to patients with no or mild I/R injury. The decrease in plasma levels of MMP-2, TIMP-1 and TIMP-2 during OLT occurred irrespective of the severity of the I/R injury. There was a significant correlation between MMP-9 and t-PA levels, but not with TNF-alpha. In conclusion, OLT is associated with a sharp increase of MMP-9 during the anhepatic and postreperfusion periods, which coincided with the changes in t-PA. MMP-2, TIMP-1 and TIMP-2 gradually decreased during OLT. The composition of these MMPs was not altered by the use of aprotinin, suggesting that serine-protease/plasmin-independent pathways are responsible for MMP regulation during OLT. In addition, only MMP-9 seems to be involved in I/R injury during human liver transplantation.
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PMID:Plasma MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 during human orthotopic liver transplantation. The effect of aprotinin and the relation to ischemia/reperfusion injury. 1498 26


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