Swaisgood Carmen M, Schmitt Detlef, Eaton Dan, Plow Edward F
Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Clin Invest. 2002 Nov;110(9):1275-82. doi: 10.1172/JCI15082.
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.
纤溶酶原（Plg）在纤维蛋白溶解和细胞迁移中的主要功能取决于其与羧基末端赖氨酰残基的结合。血浆羧肽酶B（pCPB）去除这些残基的能力表明，它可能作为这些Plg功能的抑制剂。为了评估pCPB在体内的这一作用，通过同源重组产生了纯合子pCPB缺陷小鼠，并将存活且健康的所得pCPB（-/-）小鼠与Plg（-/-）小鼠交配。与Plg野生型和缺陷型小鼠相比，Plg（+/-）小鼠的纤维蛋白溶解和细胞迁移水平处于中间状态，这反映了它们血浆中Plg抗原的中间水平。然后在Plg（+/-）背景下分析了pCPB（+/+）、pCPB（+/-）和pCPB（-/-）小鼠之间Plg依赖性功能的差异。在肺血栓溶解模型中，与野生型对应物（pCPB（+/+））相比，部分（pCPB（+/-））或完全缺乏（pCPB（-/-））pCPB的小鼠纤维蛋白溶解显著增加。在硫代乙醇酸盐诱导的腹膜炎模型中，与野生型对应物相比，Plg（+/-）/pCPB（+/-）和Plg（+/-）/pCPB（-/-）小鼠在72小时时白细胞迁移显著增加。这些研究证明了pCPB在体内作为Plg在纤维蛋白溶解和细胞迁移中的关键功能调节剂的明确作用。
