Cardiovascular disease (CVD) is the leading cause of mortality in the United States and is responsible for nearly 50% of the adult deaths. Numerous studies document the association of both inflammatory and haemostatic markers with CVD, suggesting inflammation and thrombosis are critical factors in the initiation and progression of disease CVD. Increased formation and/or decreased degradation of clots are the central events in thrombotic diseases, and the plasminogen (Plg) system is the major enzymatic network responsible for the dissolution of clots. Studies of mice in which genes for Plg and other components of the Plg system have been inactivated, have verified the crucial role of the Plg system in clot lysis and maintenance of vascular patency in vivo, and have also have implicated Plg in a number of physiological and pathological processes unrelated to clot lysis, such as infection, wound healing and of particular relevance to the pathogenesis of CVD, inflammation. Published studies and our own preliminary data show that Plg exerts a profound effect upon inflammatory cell, providing a strong link between Plg, the primary pathway for dissolution of thrombi, and inflammation, a response intimately linked to the pathogenesis of CVD. The objective of this proposed study is to determine the mechanisms by which Plg regulates leukocyte migration and, thereby, the inflammatory responses that contribute to thrombosis and CVD. Our overarching hypothesis is that Plg regulates leukocyte migration by a three step process which involves plasminogen binding and activation at cell surfaces; generation of cytokines, and then ECM remodeling. This proposal focuses on the latter two steps. At the same time, we shall test whether apo(a) influences these events and if Plg is, indeed, involved in its pathogenic activities. The following specific aims are proposed: 1). Test the hypothesis that plasmin dependent degradation of ECM, either directly or indirectly, through its activation of metalloproteinases (MMPs), is required for leukocyte recruitment in inflammatory responses in vivo utilizing wild-type (WT) and Plg-/- mice. 2). Test the hypothesis that plasmin activates endothelial cells and monocytes to produce chemoattractants for Plg dependent monocyte recruitment. Cytokine/chemokine production will be tested in WT and PIg-/-mice after injection of an inflammatory stimulus, thiolglycollate. 3). Test the hypothesis that apo(a) is a prothrombotic and anti-inflammatory stimulus. The proposed studies will provide insights into the mechanisms by which Plg controls the interface between inflammation and thrombosis and will also clarify the mechanisms by which apo(a) contributes to CVD. Plasmin-dependent therapy is utilized broadly in the treatment of thrombotic events, and our studies may provide ways to improve such therapy by suggesting the value of regulating inflammatory responses during such treatments.
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