Abstract
Zymogens are delivered to the arterial wall by radial transmural convection. Plasminogen can be activated within the arterial wall to produce plasmin, which is involved in evolution of the atherosclerotic plaque. Vascular smooth muscle cells (vSMCs) protect the vessels from proteolytic injury due to atherosclerosis development by highly expressing endocytic LDL receptor-related protein-1 (LRP-1), and by producing anti-proteases, such as Protease Nexin-1 (PN-1). PN-1 is able to form covalent complexes with plasmin. We hypothesized that plasmin-PN-1 complexes could be internalized via LRP-1 by vSMCs during the early stages of human atheroma. LRP-1 is also responsible for the capture of aggregated LDL in human atheroma. Plasmin activity and immunohistochemical analyses of early human atheroma showed that the plasminergic system is activated within the arterial wall, where intimal foam cells, including vSMCs and platelets, are the major sites of PN-1 accumulation. Both PN-1 and LRP-1 are overexpressed in early atheroma at both messenger and protein levels. Cell biology studies demonstrated an increased expression of PN-1 and tissue plasminogen activator by vSMCs in response to LDL. Plasmin-PN-1 complexes are internalized via LRP-1 in vSMCs, whereas plasmin alone is not. Tissue PN-1 interacts with plasmin in early human atheroma via two complementary mechanisms: plasmin inhibition and tissue uptake of plasmin-PN-1 complexes via LRP-1 in vSMCs. Despite this potential protective effect, plasminogen activation by vSMCs remains abnormally elevated in the intima in early stages of human atheroma.
Highlights
The arterial wall is the target of plasma-borne components such as low density lipoprotein (LDL) (Tabas et al, 2007) and circulating zymogens (Lacolley et al, 2012)
We investigated the source of Protease Nexin-1 (PN-1) in early human atheroma and the ability of vascular smooth muscle cells (vSMCs) to internalize plasmin-PN-1 complexes
Our study showed that the plasminergic system is activated within the arterial intima in early atheroma. vSMCs and platelets are the main sources of PN-1 in human atherosclerotic lesions, but the endocytosed form of PN-1 is observed, at least partly, in intimal foam cells
Summary
The arterial wall is the target of plasma-borne components such as low density lipoprotein (LDL) (Tabas et al, 2007) and circulating zymogens (Lacolley et al, 2012). Like LDL, circulating zymogens and proforms are delivered to the adjacent arterial wall by radial transmural hydraulic conductance (Caro and Lever, 1984; Caro, 2009) In addition to their role in clot lysis, tumoral cell mobilization, and metastasis (Didiasova et al, 2014), enzymes of the fibrinolytic system are involved in the chronic evolution of the plaque at the initial stage of atherosclerotic disease (Torzewski et al, 2004), including migration and loss of vascular smooth muscle cells (vSMCs) by pericellular proteolysis (Meilhac et al, 2003). VSMCs produce antiproteases to protect the vascular wall from proteolytic injury (Gomez et al, 2013) Among these antiproteases, significant quantities of serpins, such as Protease Nexin-1 (PN-1) (Bouton et al, 2003) and plasminogen activator inhibitor-1 (PAI-1), in parallel with tissue inhibitors of metalloproteinases (TIMPs), are known to be expressed by vSMCs (Bouton et al, 2012). PN-1 forms covalent complexes with its target proteases, which are cleared by endocytosis, mainly via the LDL receptor-related protein-1 (LRP1), a member of the scavenger receptor family (Knauer et al, 1997, 1999; Muhl et al, 2007; Lillis et al, 2008)
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