SERPIN regulation of factor XIa - The novel observation that protease nexin 1 in the presence of heparin is a more potent inhibitor of factor XIa than C1 inhibitor

In the present studies we have made the novel observation that protease nex in 1 (PN1), a member of the serine protease inhibitor (SERPIN) superfamily, is a potent inhibitor of the blood coagulation Factor Ma (FXIa). The inhib itory complexes formed between PN1 and FXIa are stable when subjected to re ducing agents, SDS, and boiling, a characteristic of the acyl linkage forme d between SERPINs and their cognate proteases. Using a sensitive fluorescen ce-quenched peptide substrate, the K-assoc of PN1 for FXIa was determined t o be 7.9 x 10(4) M-1 s(-1) in the absence of heparin. In the presence of he parin, this rate was accelerated to 1.7 x 10(6), M-1 s(-1), making PN1 a fa r better inhibitor of FXIa than C1 inhibitor, which is the only other SERPI N known to significantly inhibit FXIa. FXIa-PN1 complexes are shown to be i nternalized and degraded by human fibroblasts, most likely via the low dens ity lipoprotein receptor-related protein (LRP), since degradation was stron gly inhibited by the LRP agonist, receptor associated protein. Since FXIa p roteolytically modifies the amyloid precursor protein, this observation may suggest an accessory role for PN1 in the pathobiogenesis of Alzheimer's di sease.