Protein disulfide isomerase in cardiovascular disease

Abstract

Protein disulfide isomerase (PDI) participates in the pathogenesis of numerous diseases. Increasing evidence indicates that intravascular cell-derived PDI plays an important role in the initiation and progression of cardiovascular diseases, including thrombosis and vascular inflammation. Recent studies with PDI conditional knockout mice have advanced our understanding of the function of cell-specific PDI in disease processes. Furthermore, the identification and development of novel small-molecule PDI inhibitors has led into a new era of PDI research that transitioned from the bench to bedside. In this review, we will discuss recent findings on the regulatory role of PDI in cardiovascular disease.

Fig. 1. Protein folding by PDI in the ER.

Oxidizing equivalents are transferred from the active site disulfide bonds (Cys53-Cys56 and Cys397-Cys400) of oxidized PDI to the reduced substrate. In turn, PDI is reduced and reoxidized by ERO1 in the ER environment. Misfolded substrates are reduced and reoxidized or directly isomerized. The x-linker region (X) is also indicated. The highly acidic region (c) is not shown here. N and C represent the N- and C-terminus, respectively.

Fig. 2. PDI activity in the extracellular region.

As the redox environment outside the cell is reducing compared to the highly oxidizing ER environment, PDI is likely to function as a reductase in the extracellular milieu. The binding sites of some PDI inhibitors to oxidized PDI are described.