Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new rat model for investigation of the interactions of thrombin inhibitors with endogenous fibrinolysis in vivo is described. The method utilizes the thrombin-like snake enzyme batroxobin, which mainly cleaves the fibrinopeptide A from fibrinogen and activates factor XIII only to a slight degree. Compared to thrombin-formed fibrin, batroxobin-formed fibrin is more readily lysed by plasmin, since it only cross-links fibrin to a minor extent. Radiolabeled fibrinogen (125I) was given intravenously to monitor the effects of batroxobin on fibrinogen and the effects of plasmin on the fibrin formed. Batroxobin was given intravenously in a dose that converted most fibrinogen to fibrin. Five to 10 minutes after batroxobin administration, 125I-activity in the blood decreased, indicating the disappearance of fibrinogen from the circulating blood. At the same time, the 125I activity as measured with a gamma counter increased over the lungs. The fibrin formed in the microvasculature of the lungs started an endogenous fibrinolysis. This could be seen as reappearance of the 125I activity in the blood from fibrin degradation products accompanied by a decrease in the 125I activity over the lungs. When the rats were given tranexamic acid, the endogenous fibrinolysis was markedly decreased, measured as 125I activity in the blood, over the lungs and in lung parenchyma samples. The thrombin inhibitor DuP 714, which apparently inhibits not only thrombin but also plasmin and tissue plasminogen activator, completely prevented the fibrinolytic phase. The selective thrombin inhibitor argatroban, on the other hand, led to shortened lysis time. It is concluded that the present method provides a convenient and accurate means of studying pharmacological interventions with endogenous fibrinolysis. The differential effects of selective and nonselective thrombin inhibitors on endogenous fibrinolysis at comparable levels of thrombin inhibition are clearly demonstrated.
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PMID:New model for in vivo studies of pharmacological interventions with endogenous fibrinolysis: effects of thrombin inhibitors. 894 18

Batroxobin is a snake venom that is a thrombinlike enzyme used for clinical treatment. We analyzed hepatic mRNA levels for fibrinogen subunit polypeptides and prothrombin by reverse transcription-polymerase chain reaction as well as coagulation and fibrinolysis factors in plasma 1, 3, 5 and 24 hours after Batroxobin treatment (3 BU/100 g) in rats. The mRNA levels of alpha- and beta-chains of fibrinogen were significantly increased with decreases in plasma fibrinogen, alpha2-plasmin inhibitor, and plasminogen levels, while the mRNA levels for prothrombin remained unchanged. These results suggest that fibrinogen mRNA synthesis is regulated by plasma fibrinogen levels in Batroxobin-induced defibrinogenated rats.
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PMID:Changes in mRNA levels of fibrinogen subunit polypeptides in rats defibrinogenated with batroxobin. 1063 64

The activity of plasmin plays a critical role in the development of chronic glomerulonephritis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a potent inhibitor of plasmin generation. We hypothesized that TAFI is involved in the pathogenesis of glomerulonephritis because it inhibits plasmin generation. To demonstrate this hypothesis, we compared the development of immune complex-mediated glomerulonephritis in wild-type and TAFI-deficient mice. After six weeks of treatment with horse spleen apoferritin and lipoplysaccharide to induce glomerulonephritis, mice deficient in TAFI had significantly better renal function as shown by lower concentrations of albumin in urine and blood urea nitrogen compared to wild-type mice. In addition, the activity of plasmin and matrix metalloproteinases was significantly increased, and mesangial matrix expansion and the deposition of collagen and fibrin in kidney tissues were significantly decreased in TAFI-knockout mice as compared to their wild-type counterparts. Depletion of fibrinogen by batroxobin (Defibrase) treatment led to equalization of the renal function and the amount of collagen deposition in the kidneys of TAFI-knockout and wild-type mice with immune complex-mediated glomerulonephritis. Together these observations suggest that TAFI-mediated inhibition of plasmin generation plays a role in the pathogenesis of glomerulonephritis, and that it may constitute a novel molecular target for the therapy of this disease.
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PMID:Immune complex-mediated glomerulonephritis is ameliorated by thrombin-activatable fibrinolysis inhibitor deficiency. 1861 43