Protein disulfide isomerase in thrombosis and vascular inflammation

Abstract

Protein disulfide isomerase (PDI) catalyzes disulfide bond oxidation, reduction and isomerization during protein synthesis in the endoplasmic reticulum (ER). In addition to its critical role in the ER, in vitro and in vivo studies with blocking antibodies and conditional knockout mice have demonstrated that cell surface PDI is required for thrombosis, hemostasis and vascular inflammation in a manner dependent on its isomerase activity. This review will focus on our current understanding of the pathophysiologic role of PDI in regulating integrin-mediated platelet and neutrophil functions during vascular disease.

Keywords: inflammation; integrins; neutrophils; platelet; protein disulfide isomerase; thrombosis.

Fig. 1

The function and catalytic activity of protein disulfide isomerase (PDI). (A) PDI oxidizes, reduces and isomerizes disulfide bonds in substrate proteins. (B) Schematic illustration of human PDI. The catalytically active (a and a′) and inactive (b and b′) domains are shown in green and brown, respectively. Two active CGHC sequences (53 and 56, and 397 and 400) are shown in red. The x-linker region and highly acidic region (c) are indicated by a black line and light purple, respectively. The C-terminal ER retention signal (KDEL) is shown in yellow.

Fig. 2

The role of intravascular cell protein disulfide isomerase (PDI) during thrombus formation at the site of vascular injury. Following endothelial cell activation or injury, PDI is released from the activated or damaged endothelial cells, thereby supporting initial platelet adhesion and fibrin generation. Adherent and activated platelets then release PDI, which supports α_IIbβ₃ integrin-mediated platelet accumulation. Platelet-specific PDI-deficient mice show a significant defect in α_IIbβ3 integrin-mediated platelet accumulation without effects on initial platelet adhesion and fibrin generation, which would be important for hemostasis. WT, wild type.

Fig. 3

The role of neutrophil surface protein disulfide isomerase (PDI) in regulating α_Mβ₂ integrin-mediated neutrophil recruitment during vascular inflammation. Neutrophil surface PDI is present with unknown membrane molecules (white oval or square) in lipid rafts of unstimulated neutrophils. Under inflammatory conditions, α_Mβ₂ integrin with a resting (α_Mβ_2i) and/or activated (α_Mβ_2a) conformation translocates into lipid rafts and interacts with PDI. Such interaction induces thiol exchange on the α_M subunit in a manner dependent on the PDI isomerase activity, thereby facilitating clustering of activated α_Mβ₂ integrin and increasing its ligand-binding activity.