The plasminogen activation system in skeletal muscle regeneration: antagonistic roles of urokinase-type plasminogen activator (upa) and its inhibitor (PAI-1)

10.2741/1754 ◽  
2005 ◽  
Vol 10 (1-3) ◽  
pp. 2978 ◽  
Author(s):  
Monica, Suelves
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration ◽  
Plasminogen Activation ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Activation System ◽  
Pai 1

Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1703-1711 ◽  
Author(s):  
Frederic Lluı́s ◽  
Josep Roma ◽  
Mònica Suelves ◽  
Maribel Parra ◽  
Gloria Aniorte ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Plasminogen Activators ◽  
Skeletal Muscle Regeneration ◽  
Plasminogen Activation ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Deficient Mice

Plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) are extracellular proteases involved in various tissue remodeling processes. A requirement for uPA activity in skeletal myogenesis was recently demonstrated in vitro. The role of plasminogen activators in skeletal muscle regeneration in vivo in wild-type, uPA-deficient, and tPA-deficient mice is investigated here. Wild-type and tPA−/− mice completely repaired experimentally damaged skeletal muscle. In contrast, uPA−/− mice had a severe regeneration defect, with decreased recruitment of blood-derived monocytes to the site of injury and with persistent myotube degeneration. In addition, uPA-deficient mice accumulated fibrin in the degenerating muscle fibers; however, the defibrinogenation of uPA-deficient mice resulted in a correction of the muscle regeneration defect. A similar severe regeneration deficit with persistent fibrin deposition was also reproducible in plasminogen-deficient mice after injury, suggesting that fibrinolysis by uPA-mediated plasminogen activation plays a fundamental role in skeletal muscle regeneration. In conclusion, the uPA-plasmin system is identified as a critical component of the mammalian skeletal muscle regeneration process, possibly because it prevents intramuscular fibrin accumulation and contributes to the adequate inflammatory response after injury. These studies demonstrate the requirement of an extracellular proteolytic cascade during muscle regeneration in vivo.

ID: 275 The plasminogen activation system and skeletal muscle regeneration

2006 ◽  
Vol 4 (s1) ◽  
pp. 240-240
Author(s):  
B. Vidal ◽  
M. Suelves ◽  
A. Serrano ◽  
M. Tjwa ◽  
R. Lopez-Alemany ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration ◽  
Plasminogen Activation ◽  
Plasminogen Activation System ◽  
Activation System

scholarly journals Changes in the content of some components of the plasminogen activation system in the plasma of bladder cancer patients

2020 ◽  
Vol 80 (1) ◽  
pp. 15-19
Author(s):  
V. Dmytryk ◽  
O. Savchuk ◽  
P. Yakovlev
Keyword(s):  
Bladder Cancer ◽  
Blood Plasma ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Invasion And Metastasis ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Activation System ◽  
Pai 1

Bladder cancer (BC) continues to be a disease with a high mortality rate. Bladder cancer is the sixth for men and seventeenth for women in the incidence of malignancy worldwide. The invasion and metastasis of malignant tumors are caused by a sequence of processes, including loss of cell-cell and / or cell-matrix adhesion, proteolysis, and induction of angiogenesis. Different protease systems are involved in these processes, especially during the invasion and development of metastases. One such protease system is a plasminogen activation system or fibrinolysis system. Changes in the balance of plasminogen activation systems have been investigated in many types of malignancies, and these changes may not only indicate the functioning of this system but may also have prognostic significance. In malignancies, the components of this system are involved in the growth, invasion, and metastasis of tumors, affecting cell migration and angiogenesis. The main, but a well-studied component of the plasminogen activation system is serine proteinase – urokinase-type plasminogen activator (uPA). In contrast to uPA, tissue-type plasminogen activator (tPA) is characterized by a high affinity for fibrin and is involved in thrombolysis. Both types of plasminogen activators are synthesized in tumor tissues: tPA and uPA. The largest player among the inhibitors of fibrinolysis is the plasminogen activator inhibitor type 1 (PAI-1), involved in the pathogenesis of many cardiovascular diseases, as well as in cancer. The purpose of this study was to detect changes in the content of plasminogen activator tissue type tPA and PAI-1 in the blood plasma of patients with BC at different stages of the disease. The study involved 40 men who were verified with a diagnosis of BC. The content of tPA and PAI-1 in preoperative blood plasma was determined by enzyme immunoassay in ELISA modification. In our study, changes in the tPA and PAI-1 content of the blood plasma at different stages were identified, which can characterize tumor growth and invasion and can supplement existing disease information.

scholarly journals Macrophage-Specific Expression of Urokinase-Type Plasminogen Activator Promotes Skeletal Muscle Regeneration

2011 ◽  
Vol 187 (3) ◽  
pp. 1448-1457 ◽  
Author(s):  
Margaret L. Novak ◽  
Scott C. Bryer ◽  
Ming Cheng ◽  
Mai-Huong Nguyen ◽  
Kevin L. Conley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration ◽  
Specific Expression ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

scholarly journals Urokinase-type plasminogen activator increases hepatocyte growth factor activity required for skeletal muscle regeneration

Blood ◽  
2009 ◽  
Vol 114 (24) ◽  
pp. 5052-5061 ◽  
Author(s):  
Thomas H. Sisson ◽  
Mai-Huong Nguyen ◽  
Bi Yu ◽  
Margaret L. Novak ◽  
Richard H. Simon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Muscle Regeneration ◽  
Wild Type ◽  
Blocking Antibody ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Hepatocyte Growth ◽  
Pai 1

Abstract The plasminogen system plays a crucial role in the repair of a variety of tissues, including skeletal muscle. We hypothesized that urokinase-type plasminogen activator (uPA) promotes muscle regeneration by activating hepatocyte growth factor (HGF), which, in turn, stimulates proliferation of myoblasts required for regeneration. In our studies, levels of active HGF and phosphorylation of the HGF receptor c-met were increased after muscle injury in wild-type mice. Compared with wild-type animals, mice deficient in uPA (uPA−/−) had markedly reduced HGF levels and c-met activation after muscle damage. This reduced HGF activity in uPA−/− animals was associated with decreased cell proliferation, myoblast accumulation, and new muscle fiber formation. On the other hand, HGF activity was enhanced at early time points in PAI-1−/− mice compared with wild-type mice and the PAI-1−/− animals exhibited accelerated muscle fiber regeneration. Furthermore, administration of exogenous uPA rescued HGF levels and muscle regeneration in uPA−/− mice, and an HGF-blocking antibody reduced HGF activity and muscle regeneration in wild-type mice. We also found that uPA promotes myoblast proliferation in vitro through its proteolytic activity, and this process was inhibited by an HGF-blocking antibody. Together, our findings demonstrate that uPA promotes muscle regeneration through HGF activation and subsequent myoblast proliferation.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

scholarly journals The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

2021 ◽  
Vol 10 (3) ◽  
pp. 518
Author(s):  
Filomena Napolitano ◽  
Nunzia Montuori
Keyword(s):  
Plasminogen Activator ◽  
Blood Clot ◽  
Active Form ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Scientific Debate ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Normal Blood Flow

The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. The plasminogen activation (PA) system includes urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), and two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In addition to the regulation of fibrinolysis, the PA system plays an important role in other biological processes, which include degradation of extracellular matrix such as embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and immune response. Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. Different forms of angioedema are linked to uncontrolled activation of coagulation and fibrinolysis systems. Moreover, plasmin itself can induce a potentiation of bradykinin production with consequent swelling episodes. The number of studies investigating the PA system involvement in angioedema has grown in recent years, highlighting its relevance in etiopathogenesis. In this review, we present the components and diverse functions of the PA system in physiology and its importance in angioedema pathogenesis.

The urokinase-type plasminogen activator receptor is not required for skeletal muscle inflammation or regeneration

2007 ◽  
Vol 293 (3) ◽  
pp. R1152-R1158 ◽  
Author(s):  
Scott C. Bryer ◽  
Timothy J. Koh
Keyword(s):  
Skeletal Muscle ◽  
Plasminogen Activator ◽  
Muscle Regeneration ◽  
Inflammatory Cells ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

The hypothesis of this study was the urokinase-type plasminogen activator receptor (uPAR) is required for accumulation of inflammatory cells in injured skeletal muscle and for efficient muscle regeneration. Expression of uPAR was elevated at 1 and 3 days after cardiotoxin-induced muscle injury in wild-type mice before returning to baseline levels. Neutrophil accumulation peaked 1 day postinjury in muscle from both wild-type (WT) and uPAR null mice, while macrophage accumulation peaked between 3 and 5 days postinjury, with no differences between strains. Histological analyses confirmed efficient muscle regeneration in both wild-type and uPAR null mice, with no difference between strains in the formation or growth of regenerating fibers, or recovery of normal morphology. Furthermore, in vitro experiments demonstrated that chemotaxis is not different between WT and uPAR null macrophages. Finally, fusion of cultured satellite cells into multinucleated myotubes was not different between cells isolated from WT and uPAR null mice. These results demonstrate that uPAR is not required for the accumulation of inflammatory cells or the regeneration of skeletal muscle following injury, suggesting uPA can act independently of uPAR to regulate events critical for muscle regeneration.

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