P244The possible modulating role of protease nexin 1 and plasmin/plasmingen associated to ldl receptor-related protein-1 in the pathogenesis of human ascending aortic aneurysm

Abstract

Thoracic aortic aneurysm (TAA) refers to an abnormal progressive dilation of the aorta involving all 3 layers, histopathologically characterized by fibrillar extracellular matrix breakdown and the presence of large areas containing mucoid material. All this degradation is a result of the action of metalloproteinases activated via plasmin through its activators. Recently we showed: the action of the fibrinolytic system on the wall of the aorta with aneurysm, the presence of plasminogen/plasmin on the vascular smooth muscle cell (VSMC) surface and inside cytoplasmic vesicles, as well as the overexpression of protease nexin 1 (PN1). Increased expression of PN1 suggests a response of VSMCs to proteolysis by blocking the action of MMPs and thus preventing the advance of the disease. Our hypothesis is that PN-1 binds to plasmin and this complex is endocytosed via low-density lipoprotein receptor-related protein-1 (LRP-1), thus inactivating this serine-protease. This study aimed to verify the expression of LRP1 and to evaluate its possible interaction (co-location) with PN-1 and plasminogen/plasmin in the tunica media of normal and aneurysmal aortas. Sections of aortas from cases of TAA (n=4) and controls (n=4) were analyzed by immunoperoxidase and immunofluorescence to LRP-1, plasminogen/plasmin and PN-1. Sections of aortas with aneurysms showed high presence and co-localization between LRP1, plasminogen/plasmin and PN1. In contrast, normal aortas showed low presence of PN1, LRP1 and plasminogen/plasmin, it is not possible to observe a high co-location. These findings strengthen our hypothesis of endocytosis of PN1/plasmin complex via LRP1 and the modulating role of PN1 in thoracic aortic aneurysms.