Novel aspects and new roles for the serine protease plasmin

Syrovets, Tatiana; Simmet, Th.

doi:10.1007/s00018-003-3348-5

Cited by 137 publications

(155 citation statements)

References 92 publications

(119 reference statements)

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…Plasmin signaling has been recognized for some time in the context of proinflammatory activation of monocytes (41). Plasmin serves as a significant chemoattractant, inducing release of the powerful monocyte chemotactic and chemokinetic leukotriene B 4 (42-44).…”

Section: A Either Anxa2mentioning

confidence: 99%

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

He¹,

Sui

Xiong

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

In response to blood vessel injury, hemostasis is initiated by platelet activation, advanced by thrombin generation, and tempered by fibrinolysis. The primary fibrinolytic protease, plasmin, can be activated either on a fibrin-containing thrombus or on cells. Annexin A2 (A2) heterotetramer (A2⅐p11) 2 is a key profibrinolytic complex that assembles plasminogen and tissue plasminogen activator and promotes plasmin generation. We now report that, in endothelial cells, plasmin specifically induces activation of conventional PKC, which phosphorylates serine 11 and serine 25 of A2, triggering dissociation of the (A2⅐p11) 2 tetramer. The resulting free p11 undergoes ubiquitinmediated proteasomal degradation, thus preventing further translocation of A2 to the cell surface. In vivo, pretreatment of A2 ؉/؉ but not A2 ؊/؊ mice with a conventional PKC inhibitor significantly reduced thrombosis in a carotid artery injury model. These results indicate that augmentation of fibrinolytic vascular surveillance by blockade of serine phosphorylation is A2-dependent. We also demonstrate that plasmin-induced phosphorylation of A2 requires both cleavage of A2 and activation of Toll-like receptor 4 on the cell surface. We propose that plasmin can limit its own generation by triggering a finely tuned "feedback" mechanism whereby A2 becomes serine-phosphorylated, dissociates from p11, and fails to translocate to the cell surface.The human hemostatic system represents a coordinated balance between procoagulant and anticoagulant/profibrinolytic activities. Together, these systems prevent blood loss while maintaining blood flow. Plasmin, the major protease of the fibrinolytic system, acts to digest insoluble fibrin into soluble fibrin degradation products. Plasmin generation is modulated by plasminogen activators and plasminogen activator inhibitors and is further regulated by binding of plasminogen and its activators to cell surface receptors (1). Membrane-associated annexin A2 (A2) 3 is part of a heterotetrameric complex in which the N termini of two copies of A2 bind to two copies of the S100 family protein, S100A10 (p11) (2). A2, a member of the annexin superfamily, consists of a highly conserved C-terminal phospholipid-binding core domain and an N-terminal ligandinteracting domain (3). Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5-8, 52).Several lines of evidence identify the (A2⅐p11) 2 complex as a significant regulator of fibrin balance in vivo. First, A2 Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flo...

show abstract

Section: A Either Anxa2mentioning

confidence: 99%

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

He¹,

Sui

Xiong

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…16 -18 Many cells have various types of cell surface receptors for Plg, and plasmin activity generated on the cell surface plays a role for the migration of certain cells. 19,20 Thus, plasmin is important for processes that require tissue remodeling, such as angiogenesis, metastasis, wound healing, and liver regeneration. 13,14,20 -22 In infectious diseases, Plg may play a dual role.…”

mentioning

confidence: 99%

“…On one hand, Plg is used by some bacteria to invade the host 19,23,24 ; on the other hand, plasmin may be important for host defense against infection. 19,25,26 The processes previously mentioned, in which Plg plays an important role, resemble the processes involved in periodontitis. Therefore, it would be interesting to investigate the role of Plg in periodontitis.…”

mentioning

confidence: 99%

Plasmin Is Essential in Preventing Periodontitis in Mice

Sulniute

Lindh

Wilczyńska

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue-and urokinase-type plasminogen activators, developed periodontal disease similar to that in Plg-deficient mice; however, mice lacking only tissueor urokinase-type plasminogen activator remained healthy. Supplementation by injection of Plg-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Plg-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases.

show abstract

“…T he urokinase-type plasminogen activator (uPA)/plasminogen (Plg) system mediates numerous important biological processes including fibrinolysis, ECM and growth factor metabolism, cell migration, and inflammation (1,2). Because all of these processes affect the development of atherosclerosis and because the critical components of the uPA/Plg system [i.e., uPA, the uPA receptor (uPAR), and Plg] are present in the artery wall, several groups have investigated the role of the uPA/Plg system in atherogenesis (1,3).…”

mentioning

confidence: 99%

Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice

Kremen

Krishnan

Emery

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Urokinase-type plasminogen activator (uPA) is expressed at elevated levels in atherosclerotic human arteries, primarily in macrophages. Plasminogen (Plg), the primary physiologic substrate of uPA, is present at significant levels in blood and interstitial fluid. Both uPA and Plg have activities that could affect atherosclerosis progression. Moreover, correlations between increased Plg activation and accelerated atherosclerosis are reported in several human studies. However, a coherent picture of the role of the uPA/Plg system in atherogenesis has not yet emerged, with at least one animal study suggesting that Plg is atheroprotective. We used a transgenic mouse model of macrophage-targeted uPA overexpression in apolipoprotein E-deficient mice to investigate the roles of uPA and Plg in atherosclerosis. We found that macrophageexpressed uPA accelerated atherosclerotic plaque growth and promoted aortic root dilation through Plg-dependent pathways. These pathways appeared to affect lesion progression rather than initiation and to include actions that disproportionately increase lipid accumulation in the artery wall. In addition, loss of Plg was protective against atherosclerosis both in the presence and absence of uPA overexpression. Transgenic mice with macrophagetargeted uPA overexpression reveal atherogenic roles for both uPA and Plg and are a useful experimental setting for investigating the molecular mechanisms that underlie clinically established relationships between uPA expression, Plg activation, and atherosclerosis progression.proteolysis ͉ aorta ͉ aneurysm

show abstract

Novel aspects and new roles for the serine protease plasmin

Cited by 137 publications

References 92 publications

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

Plasmin Is Essential in Preventing Periodontitis in Mice

Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice

Contact Info

Product

Resources

About