Inflammation plays a critical role in the development of cardiovascular diseases. Infiltration of leukocytes to sites of injury requires their exit from the blood and migration across basement membrane; this process has been postulated to require remodeling of the ECM. Plasminogen (Plg) is a protease that binds to the ECM and, upon conversion to plasmin, degrades multiple ECM proteins. In addition, plasmin directly activates MMPs. Here, we used Plg -/-mice to investigate the role of Plg in inflammatory leukocyte migration. After induction of peritonitis by thioglycollate injection, we found that Plg -/-mice displayed diminished macrophage trans-ECM migration and decreased MMP-9 activation. Furthermore, injection of the active form of MMP-9 in Plg -/-mice rescued macrophage migration in this model. We used periaortic application of CaCl 2 to induce abdominal aortic aneurysm (AAA) and found that Plg -/-mice displayed reduced macrophage infiltration and were protected from aneurysm formation. Administration of active MMP-9 to Plg -/-mice promoted macrophage infiltration and the development of AAA. These data suggest that Plg regulates macrophage migration in inflammation via activation of MMP-9, which, in turn, regulates the ability of the cells to migrate across ECM. Thus, targeting the Plg/MMP-9 pathway may be an attractive approach to regulate inflammatory responses and AAA development.

The plasminogen system plays a pivotal role in maintaining vascular patency and in cell migration. Binding of plasminogen to surfaces (i.e., fibrin or cells) is of crucial importance in regulating the function of this system. Plasmin(ogen) binds to cells with low affinity and high capacity via its lysine binding sites, which are associated with its kringle domains and recognize carboxy-terminal lysines of cell surface proteins. Upon binding to cellular receptors, plasminogen is more readily activated; bound plasmin has increased enzymatic activity and is protected from inactivation by inhibitors. Plasminogen receptors are modulated by numerous factors, including proteases, steroid hormones, cytokines and the adhesive state of the cells. The apoprotein(a) moiety of lipoprotein(a) is remarkably similar in amino acid sequence to plasminogen. Shared binding sites for lipoprotein(a) and plasmin(ogen) on cell surfaces and in the subendothelial matrix may contribute to the pathogenetic risks associated with elevated levels of lipoprotein(a).

Lipoprotein(a) [Lp(a)] resembles low-density lipoprotein (LDL), with an LDL lipid core and apolipoprotein B (apoB), but contains a unique apolipoprotein, apo(a). Elevated Lp(a) is an independent risk factor for coronary and peripheral vascular diseases. The size and concentration of plasma Lp(a) is related to the synthetic rate, not the catabolic rate, and is highly variable with small isoforms associated with high concentrations and pathogenic risk. Apo(a) is synthesized in the liver, although assembly of apo(a) and LDL may occur in the hepatocytes or plasma. While the uptake and clearance site of Lp(a) is poorly delineated, the kidney is the site of apo(a) fragment excretion. The structure of apo(a) has high homology to plasminogen, the zymogen for plasmin and the primary clot lysis enzyme. Apo(a) interferes with plasminogen binding to C-terminal lysines of cell surface and extracellular matrix proteins. Lp(a) and apo(a) inhibit fibrinolysis and accumulate in the vascular wall in atherosclerotic lesions. The pathogenic role of Lp(a) is not known. Small isoforms and high concentrations of Lp(a) are found in healthy octogenarians that suggest Lp(a) may also have a physiological role. Studies of Lp(a) function have been limited since it is not found in commonly studied small mammals. An important aspect of Lp(a) metabolism is the modification of circulating Lp(a), which has the potential to alter the functions of Lp(a). There are no therapeutic drugs that selectively target elevated Lp(a), but a number of possible agents are being considered. Recently, new modifiers of apo(a) synthesis have been identified. This review reports the regulation of Lp(a) metabolism and potential sites for therapeutic targets.