UMR 1148, Laboratory for Vascular Translational Science, Inserm; Paris7 Denis Diderot University.
Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Department of Biological science, Federal University of São Paulo, São Paulo, Brazil.
Cardiovasc Pathol. 2018 Jan-Feb;32:15-25. doi: 10.1016/j.carpath.2017.10.002. Epub 2017 Oct 24.
Plasminogen is a circulating zymogen which enters the arterial wall by radial, transmural hydraulic conductance, where it is converted to plasmin by tissue plasminogen activator t-PA on an activation platform involving S100A4 on the vascular smooth muscle cell (vSMC) membrane. Plasmin is involved in the progression of human thoracic aneurysm of the ascending aorta (TAA). vSMCs protect the TAA wall from plasmin-induced proteolytic injury by expressing high levels of antiproteases. Protease nexin-1 (PN-1) is a tissue antiprotease belonging to the serpin superfamily, expressed in the vascular wall, and is able to form a covalent complex with plasmin. LDL receptor-related protein-1 (LRP-1) is a scavenger receptor implicated in protease-antiprotease complex internalization. In this study, we investigated whether PN-1 and LRP-1 are involved in the inhibition and clearance of plasminogen by the SMCs of human TAA. We demonstrated an overexpression of S100A4, PN-1, and LRP-1 in the medial layer of human TAA. Plasminogen activation taking place in the media of TAA was revealed by immunohistochemical staining and plasmin activity analyses. We showed by cell biology studies that plasmin-PN-1 complexes are internalized via LRP-1 in vSMCs from healthy and TAA media. Thus, two complementary mechanisms are involved in the protective role of PN-1 in human TAA: one involving plasmin inhibition and the other involving tissue clearance of plasmin-PN1 complexes via the scavenger receptor LRP-1.
纤溶酶原是一种循环酶原，通过径向、跨壁水力传导进入动脉壁，在那里它被组织纤溶酶原激活物 t-PA 转化为纤溶酶，这涉及到血管平滑肌细胞 (vSMC) 膜上的 S100A4 激活平台。纤溶酶参与了人类升主动脉胸动脉瘤（TAA）的进展。vSMCs 通过表达高水平的抗蛋白酶来保护 TAA 壁免受纤溶酶诱导的蛋白水解损伤。蛋白酶原 1（PN-1）是一种组织抗蛋白酶，属于丝氨酸蛋白酶抑制剂超家族，在血管壁中表达，并能够与纤溶酶形成共价复合物。低密度脂蛋白受体相关蛋白-1（LRP-1）是一种参与蛋白酶-抗蛋白酶复合物内化的清道夫受体。在这项研究中，我们研究了 PN-1 和 LRP-1 是否参与了人 TAA 中 SMC 对纤溶酶原的抑制和清除。我们证明了 S100A4、PN-1 和 LRP-1 在人 TAA 的中膜层过度表达。通过免疫组织化学染色和纤溶酶活性分析揭示了 TAA 中膜层的纤溶酶原激活。我们通过细胞生物学研究表明，纤溶酶-PN-1 复合物通过 LRP-1 被内吞到来自健康和 TAA 介质的 vSMCs 中。因此，两种互补机制参与了 PN-1 在人 TAA 中的保护作用：一种涉及纤溶酶抑制，另一种涉及通过清道夫受体 LRP-1 组织清除纤溶酶-PN1 复合物。
