Abstract
Background: Thiol isomerases are a family of endoplasmic reticulum enzymes which orchestrate redox-based modifications of protein disulphide bonds. Previous studies have identified important roles for the thiol isomerases PDI and ERp5 in the regulation of normal platelet function. Aim: Recently, we demonstrated the presence of a further five thiol isomerases at the platelet surface. In this report we aim to report the role of one of these enzymes – ERp57 in the regulation of platelet function. Methods/Results: Using enzyme activity function blocking antibodies, we demonstrate a role for ERp57 in platelet aggregation, dense granule secretion, fibrinogen binding, calcium mobilisation and thrombus formation under arterial conditions. In addition to the effects of ERp57 on isolated platelets, we observe the presence of ERp57 in the developing thrombus in vivo. Furthermore the inhibition of ERp57 function was found to reduce laser-injury induced arterial thrombus formation in a murine model of thrombosis. Conclusions: These data suggest that ERp57 is important for normal platelet function and opens up the possibility that the regulation of platelet function by a range of cell surface thiol isomerases may represent a broad paradigm for the regulation of haemostasis and thrombosis.
Highlights
Platelets contain a number of thiol isomerase enzymes; PDI [1], ERp5 [2], ERp57, ERp72, ERp44, ERp29 and TMX3 [3]
In this study, using enzyme activity blocking antibodies, we demonstrate for the first time that cell-surface ERp57 is a key player in the regulation of normal platelet aggregation, integrin activation and signalling
As observed previously for ERp5 [2], affinity purification of anti-ERp57 IgG enabled the selection of potent and enzyme-selective inhibitory antibodies which were used to assess the role of ERp57 in platelet regulation
Summary
Platelets contain a number of thiol isomerase enzymes; PDI [1], ERp5 [2], ERp57, ERp72, ERp44, ERp29 and TMX3 [3]. Enzyme activity blocking antibodies raised against PDI and ERp5 have been used to demonstrate that the activity of these enzymes contributes to a range of platelet responses including aggregation, adhesion, granule secretion and integrin activation [2,5,6,7]. In this study we investigate the role of the recently identified platelet-surface thiol isomerase, ERp57 in human platelet responses and thrombus formation. In this study, using enzyme activity blocking antibodies, we demonstrate for the first time that cell-surface ERp57 is a key player in the regulation of normal platelet aggregation, integrin activation and signalling. ERp57 is secreted upon vascular injury and accumulates in the thrombus where it regulates the activation and recruitment of other platelets
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