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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078701-04
Application #
7273622
Study Section
Special Emphasis Panel (ZHL1-CSR-I (S1))
Program Officer
Sarkar, Rita
Project Start
2004-09-24
Project End
2008-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2007
Total Cost
$290,143
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Gong, Yanqing; Zhao, Yujing; Li, Ying et al. (2014) Plasminogen regulates cardiac repair after myocardial infarction through its noncanonical function in stem cell homing to the infarcted heart. J Am Coll Cardiol 63:2862-72
Huang, Menggui; Gong, Yanqing; Grondolsky, Jessica et al. (2014) Lp(a)/apo(a) modulate MMP-9 activation and neutrophil cytokines in vivo in inflammation to regulate leukocyte recruitment. Am J Pathol 184:1503-17
Hoover-Plow, Jane; Sa, Qila; Huang, Menggui et al. (2013) Genetic dissection of quantitative trait Loci for hemostasis and thrombosis on mouse chromosomes 11 and 5 using congenic and subcongenic strains. PLoS One 8:e77539
Hoover-Plow, Jane; Huang, Menggui (2013) Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 62:479-91
Hoover-Plow, Jane; Gong, Yanqing (2012) Challenges for heart disease stem cell therapy. Vasc Health Risk Manag 8:99-113
Gong, Yanqing; Fan, Yi; Hoover-Plow, Jane (2011) Plasminogen regulates stromal cell-derived factor-1/CXCR4-mediated hematopoietic stem cell mobilization by activation of matrix metalloproteinase-9. Arterioscler Thromb Vasc Biol 31:2035-43
Hoover-Plow, Jane (2010) Does plasmin have anticoagulant activity? Vasc Health Risk Manag 6:199-205
Sa, Qila; Hart, Erika; Nadeau, Joseph H et al. (2010) Mouse chromosome 17 candidate modifier genes for thrombosis. Mamm Genome 21:337-49
Hoover-Plow, Jane; Hart, Erika; Gong, Yanqing et al. (2009) A physiological function for apolipoprotein(a): a natural regulator of the inflammatory response. Exp Biol Med (Maywood) 234:28-34
Hoover-Plow, J L; Gong, Y; Shchurin, A et al. (2008) Strain and model dependent differences in inflammatory cell recruitment in mice. Inflamm Res 57:457-63

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