In vivo regulation of plasminogen function by plasma carboxypeptidase B

Swaisgood, Carmen M.; Schmitt, Detlef; Eaton, Dan; Plow, Edward F.

doi:10.1172/jci0215082

Cited by 80 publications

(53 citation statements)

References 61 publications

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“…However, contradictory reports identifying low TAFI concentrations as a risk factor for stroke and myocardial infarction have also been published [28]–[30]. While excessive TAFI levels could foster thrombosis by inducing a hypofibrinolytic state, the inverse association between reduced TAFI concentrations and higher numbers of thrombotic events might by a consequence of enhanced inflammation since the anti-inflammatory properties of TAFI are well established [28], [31]–[33]. The finding that C-reactive protein (CRP) antigen levels parallel the course of TAFI both in the acute (increase) and later phase (decrease) of ischemic stroke further support an association between hemostasis and inflammation in this disease [25].…”

Section: Discussionmentioning

confidence: 99%

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

et al. 2010

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BackgroundThrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice.Methodology/Principal Findings TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes were measured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p>0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO.ConclusionOur study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.

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Section: Discussionmentioning

confidence: 99%

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

et al. 2010

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“…Notably, macrophage recruitment to the peritoneum is suppressed by the lysine analog, tranexamic acid (Gong, Hart, Shchurin & Hoover-Plow, 2008), suggesting that plasminogen binding to cellular receptors plays a role in macrophage recruitment. Most tellingly, plasminogen-dependent macrophage recruitment in vivo is mediated by CpB-sensitive plasminogen receptors (Swaisgood et al, 2002). The roles of specific plasminogen receptors in macrophage recruitment are discussed below in Section 9.1.…”

Section: Role Of Plasminogen In Macrophage Recruitment In Vivomentioning

confidence: 99%

“…The thioglycollate-induced model of macrophage recruitment originally demonstrated the key role of plasminogen receptors with C-terminal lysines in cell migration in the inflammatory response in vivo (Swaisgood, Schmitt, Eaton & Plow, 2002). The high number of plasminogen binding sites/cell taken together with the diversity of cell types that bind plasminogen (Miles, Levin, Plescia, Collen & Plow, 1988b) suggests that the plasminogen binding capacity of a given cell may be composed of contributions from a set of distinct cell surface proteins and that different cell types may utilize a different panel of plasminogen receptors [recently reviewed by Plow and colleagues in (Plow et al, 2012)].…”

Section: Interplay Among Plasminogen Receptors In the Macrophage Mmentioning

confidence: 99%

New Insights into the Role of Plg-RKT in Macrophage Recruitment

Miles

Lighvani

Baik

et al. 2014

International Review of Cell and Molecular Biology

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Plasminogen is the zymogen of plasmin, the major enzyme that degrades fibrin clots. In addition to its binding and activation on fibrin clots, plasminogen also specifically interacts with cell surfaces where it is more efficiently activated by plasminogen activators, compared with the reaction in solution. This results in association of the broad spectrum proteolytic activity of plasmin with cell surfaces that functions to promote cell migration. Here we review emerging data establishing a role for plasminogen, plasminogen receptors and the newly discovered plasminogen receptor, Plg-RKT, in macrophage recruitment in the inflammatory response and we address mechanisms by which the interplay between plasminogen and its receptors regulates inflammation.

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“…Furthermore, plasminogen-dependent macrophage recruitment is mediated by CpB-sensitive plasminogen-binding sites [21]. …”

Section: Introductionmentioning

confidence: 99%

The Plasminogen Receptor, , and Macrophage Function

Miles

Lighvani

Baik

et al. 2012

Journal of Biomedicine and Biotechnology

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When plasminogen binds to cells its activation to plasmin is markedly enhanced compared to the reaction in solution. Thus, cells become armed with the broad spectrum proteolytic activity of plasmin. Cell-surface plasmin plays a key role in macrophage recruitment during the inflammatory response. Proteins exposing basic residues on the cell surface promote plasminogen activation on eukaryotic cells. We have used a proteomics approach combining targeted proteolysis with carboxypeptidase B and multidimensional protein identification technology, MudPIT, and a monocyte progenitor cell line to identify a novel transmembrane protein, the plasminogen receptor, Plg-RKT. Plg-RKT exposes a C-terminal lysine on the cell surface in an orientation to bind plasminogen and promote plasminogen activation. Here we review the characteristics of this new protein, with regard to membrane topology, conservation of sequence across species, the role of its C-terminus in plasminogen binding, its function in plasminogen activation, cell migration, and its role in macrophage recruitment in the inflammatory response.

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In vivo regulation of plasminogen function by plasma carboxypeptidase B

Cited by 80 publications

References 61 publications

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke

New Insights into the Role of Plg-RKT in Macrophage Recruitment

The Plasminogen Receptor, , and Macrophage Function

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