In vivo regulation of plasminogen function by plasma carboxypeptidase B

Abstract

The major functions of plasminogen (Plg) in fibrinolysis and cell migration depend on its binding to carboxy-terminal lysyl residues. The ability of plasma carboxypeptidase B (pCPB) to remove these residues suggests that it may act as a suppressor of these Plg functions. To evaluate this role of pCPB in vivo, homozygote pCPB-deficient mice were generated by homologous recombination, and the resulting pCPB -/-mice, which were viable and healthy, were mated to Plg -/-mice. Plg +/-mice show intermediate levels of fibrinolysis and cell migration compared with Plg wild-type and deficient mice, reflecting the intermediate levels of the Plg antigen in their plasma. Differences in Plg-dependent functions between pCPB +/+ , pCPB +/-, and pCPB -/-mice were then analyzed in a Plg +/-background. In a pulmonary clot lysis model, fibrinolysis was significantly increased in mice with partial (pCPB +/-) or total absence (pCPB -/-) of pCPB compared with their wild-type counterparts (pCPB +/+ ). In a thioglycollate model of peritoneal inflammation, leukocyte migration at 72 hours increased significantly in Plg +/-/pCPB +/-and Plg +/-/pCPB -/-compared with their wild-type counterparts. These studies demonstrate a definitive role of pCPB as a modulator of the pivotal functions of Plg in fibrinolysis and cell migration in vivo.