The plasminogen (Plg) system is the major enzymatic network responsible for the dissolution of clots. In addition, substantial evidence in the last few years is mounting for a critical role of the Plg system in recruitment of inflammatory cells, thereby providing a clear and direct link between thrombosis and inflammation. The overall objective of this proposal is to determine the mechanisms by which Plg regulates cell migration. Utilizing Plg deficient (Plg-/-) mice in peritonitis and abdominal aortic aneurysm (AAA) models, our studies provide in vivo evidence that Plg/plasmin is required for macrophage recruitment and this role is mediated through activation of MMP-9. In addition, Lp(a), an independent risk factor for cardiovascular disease (CVD), is shown not only to interfere with the functions of Plg by virtue of their structural similarities but also to suppress neutrophil recruitment during inflammation, an effect that is shown to be Plg independent and cytokine dependent using Plg-/- mice expressing apo(a). In our recent studies, we examined the role of Plg in stem cell mobilization (HSC) from bone marrow (BM). HSC emigration was found to be Plg dependent, and after cytokine stimulation was found to be dependent on MMP-9 activation and degradation of BM SDF-1, the primary chemoattractant of HSC. These findings identify a novel pathway for the regulation of HSC egress that has not been reported. Our hypothesis is that Plg regulates inflammatory and HSC cell migration, by non- fibrinolytic proteolysis of ECM or activation of metalloproteinases. The following Specific Aims are proposed to test this hypothesis: 1) Plg Regulation of Leukocyte Migration: determine if Plm- dependent activation of MMP-9 is direct or involves intermediate step;assess whether a MMP inhibitor contributes to the suppression of macrophage migration in Plg-/- mice;and determine the basis of Plg-dependent recruitment of inflammatory cells other than macrophages in AAA. 2) Apo(a) Plg-Dependent and Independent Regulation of Leukocyte Migration: determine if apo(a) alters the expression or activity of the neutrophil chemoattractants;determine if the anti- inflammatory effects of apo(a) on neutrophil recruitment are due to inhibition of ECM degradation;and determine whether apo(a) suppresses neutrophil infiltration into the vessel wall after injury in apo(a) transgenic mice in Plg-replete or Plg-deficient backgrounds and in a human apoB (huapoB) background that allows for assembly of Lp(a). 3) Plg Regulation of Stem Cell Mobilization: determine the role of Plg-dependent activation of MMP-9 in HSC egress from BM;determine the degradation of SDF-1;determine whether Plg-dependent HSC mobilization is required for cardiac repair;and determine whether plasmin therapy enhances HSC-mediated repair after myocardial infarction. Overall, these studies will definitively establish the roles, mechanisms and significance of Plg and Lp(a) in physiologically relevant models of cardiovascular diseases. Public Health Relevance: Cardiovascular diseases are the number one cause of death in the US. This proposal addresses the basis for plasminogen in inflammation or white cell recruitment and stem cell mobilization. Inflammation is important in the initiation of disease recovery and stem cell mobilization is a new emerging therapy for cardiovascular diseases.
In the United States, cardiovascular disease is the leading cause of death, and the association of thrombosis and inflammation with CVD has been documented in numerous studies. The objective of this proposal is to determine the mechanisms by which plasminogen regulates cell migration and, thereby, the inflammatory responses that contribute to thrombosis and CVD.
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