Regulatory role of thiol isomerases in thrombus formation

ABSTRACT

Introduction: The protein disulfide isomerase (PDI) family of thiol isomerases are intracellular enzymes known to catalyze the oxidation, reduction and isomerization of disulfide bonds during protein synthesis in the endoplasmic reticulum. PDI and related members of the thiol isomerase family are known to localize extracellularly where they possess various functions. Among these, the role of PDI in the initiation of thrombus formation is best characterized. PDI is secreted within seconds from activated platelets and endothelial cells at the site of vascular injury and accumulates in the developing platelet-fibrin thrombus. Inhibition of PDI by antibodies or small molecule inhibitors blocks thrombus formation. Efforts are underway to identify extracellular substrates of PDI that participate in the network pathways linking thiol isomerases to thrombus formation. ERp57, ERp5 and ERp72 also play a role in initiation of thrombus formation but their specific extracellular substrates are unknown.

Areas covered: The following review gives an overview of biochemistry of vascular thiol isomerases followed by a detailed description of their role in thrombosis and its clinical implications.

Expert commentary: The thiol isomerase system, by controlling the initiation of thrombus formation, provides the regulatory switch by which the normal vasculature is protected under physiologic conditions from thrombi generation.

KEYWORDS:

• Anti-thrombotic drugs
• disulfide
• endothelium
• isomerase
• oxidase
• platelet
• protein disulfide
• reductase
• thiol isomerases
• thrombus formation

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the National Institutes of Health (U54 HL112302; R01 HL136394).