Abstract
Human α2-antiplasmin (α2AP), also known as α2-plasmin inhibitor, is the major inhibitor of the proteolytic enzyme plasmin that digests fibrin. There are 2 N-terminal forms of α2AP that circulate in human plasma: a 464-residue protein with Met as the N-terminus, Met-α2AP, and a 452-residue version with Asn as the N-terminus, Asn-α2AP. We have discovered and purified a proteinase from human plasma that cleaves the Pro12-Asn13 bond of Met-α2AP to yield Asn-α2AP and have named it antiplasmin-cleaving enzyme (APCE). APCE is similar in primary structure and catalytic properties to membrane-bound fibroblast activation protein/seprase for which a physiologic substrate has not been clearly defined. We found that Asn-α2AP becomes cross-linked to fibrin by activated factor XIII approximately 13 times faster than native Met-α2AP during clot formation and that clot lysis rates are slowed in direct proportion to the ratio of Asn-α2AP to Met-α2AP in human plasma. We conclude that APCE cleaves Met-α2AP to the derivative Asn-α2AP, which is more efficiently incorporated into fibrin and consequently makes it strikingly resistant to plasmin digestion. APCE may represent a new target for pharmacologic inhibition, since less generation and incorporation of Asn-α2AP could result in a more rapid removal of fibrin by plasmin during atherogenesis, thrombosis, and inflammatory states.
Circulating FGF21 proteolytic processing mediated by fibroblast activation protein
