Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation

Holbrook, Lisa-Marie; Watkins, Nicholas A.; Simmonds, A. D.; Jones, Chris I.; Ouwehand, Willem H.; Gibbins, Jonathan M.

doi:10.1111/j.1365-2141.2009.07994.x

Cited by 87 publications

(104 citation statements)

References 43 publications

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“…Activated platelets release PDI and a pool of PDI is found at the platelet cell surface [5]. More recently it has become clear that a range of thiol isomerase enzymes (including PDI, ERp57 and ERp5) become available at the platelet surface following activation [6]. Experiments using mouse models of thrombus formation have highlighted a critical role for PDI [7][8][9], or its close homologue ERp57 (10), in platelet accumulation and fibrin deposition [11] .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

Smith

Shah²,

Kamaludin

et al. 2015

Thrombosis Research

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Introduction: Cell surface thiol isomerase enzymes, principally protein disulphide isomerase (PDI), have emerged as important regulators of platelet function and tissue factor activation via their action on allosteric disulphide bonds. Allosteric disulphides are present in other haemostasis-related proteins, and we have therefore investigated whether thiol isomerase inhibition has any influence on two endothelial activities relevant to haemostatic regulation, namely activation of protein C and activation of plasminogen, with subsequent fibrinolysis.

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Section: Introductionmentioning

confidence: 99%

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

Smith

Shah²,

Kamaludin

et al. 2015

Thrombosis Research

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“…41 Several other groups subsequently demonstrated that thiol isomerases traffic to secretory granules/membrane systems and are released from platelets in an activation-dependent manner. 36,[42][43][44][45] Kim et al showed that platelets lacking PDI have reduced activation-dependent aggregation. 46 Platelet surface PDI has been postulated to modulate a IIb b 3 function, 47 Thiol isomerases have also been found on the surface of the endothelium.…”

Section: Vascular Thiol Isomerasesmentioning

confidence: 99%

Vascular thiol isomerases

Flaumenhaft

Furie

2016

Blood

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Thiol isomerases are multifunctional enzymes that influence protein structure via their oxidoreductase, isomerase, and chaperone activities. These enzymes localize at high concentrations in the endoplasmic reticulum of all eukaryotic cells where they serve an essential function in folding nascent proteins. However, thiol isomerases can escape endoplasmic retention and be secreted and localized on plasma membranes. Several thiol isomerases including protein disulfide isomerase, ERp57, and ERp5 are secreted by and localize to the membranes of platelets and endothelial cells. These vascular thiol isomerases are released following vessel injury and participate in thrombus formation. Although most of the activities of vascular thiol isomerases that contribute to thrombus formation are yet to be defined at the molecular level, allosteric disulfide bonds that are modified by thiol isomerases have been described in substrates such as αIIbβ3, αvβ3, GPIbα, tissue factor, and thrombospondin. Vascular thiol isomerases also act as redox sensors. They respond to the local redox environment and influence S-nitrosylation of surface proteins on platelets and endothelial cells. Despite our rudimentary understanding of the mechanisms by which thiol isomerases control vascular function, the clinical utility of targeting them in thrombotic disorders is already being explored in clinical trials.

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“…Several thiol reductases have been identified in vascular cells and may be released into the extravascular space. To evaluate the selectivity of quercetin-3-rutinoside for PDI, we determined its activity against other oxidoreductases (1) known to be secreted from platelets or endothelial cells (17). Quercetin-3-rutinoside failed to inhibit ERp5, ERp57, ERp72, thioredoxin ( Figure 3A), or thioredoxin reductase ( Figure 3B).…”

Section: Introductionmentioning

confidence: 99%

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Jasuja

Passam²,

Kennedy³

et al. 2012

J. Clin. Invest.

262

345

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Thrombosis, or blood clot formation, and its sequelae remain a leading cause of morbidity and mortality, and recurrent thrombosis is common despite current optimal therapy. Protein disulfide isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Here, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high-throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Cellular assays showed that quercetin-3-rutinoside inhibited aggregation of human and mouse platelets and endothelial cell-mediated fibrin generation in human endothelial cells. Using intravital microscopy in mice, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove to be a useful adjunct in refractory thrombotic diseases that are not controlled with conventional antithrombotic agents.

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Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation

Cited by 87 publications

References 43 publications

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

Inhibition of thiol isomerase activity diminishes endothelial activation of plasminogen, but not of protein C

Vascular thiol isomerases

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

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