Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 547

Table 9.27. Plasminogen activator inhibitors (PAI) are serpins (serine peptidase inhibitor).
Plasminogen activator inhibitor-1 is mainly produced by vascular endothelial cells, hence its
other name endothelial plasminogen activator inhibitor (ePAI). It is also liberated from other cell
types such as adipocytes. It is the principal inhibitor of the serine peptidases tissue plasminogen
activator (tPA) and urokinase (uPA), the activators of plasminogen and hence of fibrinolysis.
Peptidase nexin-1 (PN1), synthesized by most cell types, such as fibroblasts, monocytes, platelets,
and vascular cells, is also called plasminogen activator inhibitor type-1 member 2. It strongly
inhibits plasminogen activators (tPA and uPA), plasmin, and thrombin. It has a high affinity for
glycosaminoglycans such as heparan sulfates. Upon heparin binding, it is a better inhibitor of blood
coagulation factor XIa than C1 inhibitor, or serpin-G1. It interacts with low-density lipoprotein
receptor-related proteins (LRP). During embryogenesis and postnatal development, it is expressed
prominently in remodeling regions, in which cell fate specification is influenced by morphogens
such as sonic Hedgehog. Plasminogen activator inhibitor-2 (PAI2) is secreted in significant
amounts by the placenta (hence its name placental plasminogen activator inhibitor [pPAI]).
However, it is synthesized in many cell types, especially monocytes and activated macrophages.
Two forms of PAI2 exist: 60-kDa, extracellular, glycosylated and 43-kDa, intracellular form.
Plasminogen activator inhibitor-3 (PAI3) is the acrosomal serine peptidase inhibitor, or protein-
C inhibitor (ProCI). It has an affinity for heparin, oxidized phosphatidylethanolamine, and
oxidized and unoxidized phosphatidylserine. Antithrombin-3 (AT3) is another heparin-binding
serpin produced by the liver that inactivates several enzymes of the coagulation cascade, such as
activated factor II and VII of the tissue factor (extrinsic) pathway as well as activated factor IX, X,
XI, and XII of the contact activation (intrinsic) pathway. It also inactivates kallikrein and plasmin
as well as trypsin and C1s subunit of the classical complement pathway. Its activity is increased by
heparin.

Subtype Aliases

PAI1 Serpin-E1, ePAI

PAI2 Serpin-B2, pPAI

PAI3 Serpin-A5, ProCI

Nexin Serpin-E2, PN1

AT3 Serpin-C1

The thrombin-thrombomodulin complex activates carboxypeptidase-B2
(CPb2). 121 The latter is a plasminogen-bound zymogen. This enzyme inactivates
vasoactive peptides such as complement C5a. When it is activated by proteolysis
(Arg92) by the thrombin-thrombomodulin complex, CPb2 removes fibrin
C-terminus that binds and activates plasminogen. Furthermore, thrombomodulin
inhibits high-mobility group box 1 DNA-binding protein HMGB1 122 that has
cytokine-like activity [ 1002 ]. Thrombomodulin thus hampers overstimulation of the

121 A.k.a. thrombin-activable fibrinolysis inhibitor [TAFI], plasma carboxypeptidase-B [pCPb], and
carboxypeptidase-U [CPu]).
122 A.k.a. amphoterin.