Regulation of Leukocyte Migration by Plasminogen

Summary

Principal Investigator: JANE LEE HOOVER-PLOW
Abstract: DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.
Funding Period: 2004-09-24 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice
    Yanqing Gong
    Joseph J Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA
    J Clin Invest 118:3012-24. 2008
  2. pmc Genetic dissection of quantitative trait Loci for hemostasis and thrombosis on mouse chromosomes 11 and 5 using congenic and subcongenic strains
    Jane Hoover-Plow
    Department of Cardiovascular Medicine and Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Clinic, Lerner Research Institute, Cleveland, Ohio, United States of America
    PLoS ONE 8:e77539. 2013
  3. pmc Lipoprotein(a) metabolism: potential sites for therapeutic targets
    Jane Hoover-Plow
    J J Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44139, USA
    Metabolism 62:479-91. 2013
  4. pmc Challenges for heart disease stem cell therapy
    Jane Hoover-Plow
    Departmentof Cardiovascular Medicine, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
    Vasc Health Risk Manag 8:99-113. 2012
  5. pmc Plasminogen regulates stromal cell-derived factor-1/CXCR4-mediated hematopoietic stem cell mobilization by activation of matrix metalloproteinase-9
    Yanqing Gong
    Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
    Arterioscler Thromb Vasc Biol 31:2035-43. 2011
  6. pmc Mouse chromosome 17 candidate modifier genes for thrombosis
    Qila Sa
    Departments of Cardiovascular Medicine and Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, OH, 44195, USA
    Mamm Genome 21:337-49. 2010
  7. pmc Does plasmin have anticoagulant activity?
    Jane Hoover-Plow
    Joseph J Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio 44195, USA
    Vasc Health Risk Manag 6:199-205. 2010
  8. pmc A physiological function for apolipoprotein(a): a natural regulator of the inflammatory response
    Jane Hoover-Plow
    Department of Molecular Cardiology, NB50, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Exp Biol Med (Maywood) 234:28-34. 2009
  9. pmc Strain and model dependent differences in inflammatory cell recruitment in mice
    J L Hoover-Plow
    Department of Cardiovascular Medicine and Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, NB50, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
    Inflamm Res 57:457-63. 2008
  10. pmc Quantitative trait locus analysis for hemostasis and thrombosis
    Qila Sa
    Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland, OH 44195, USA
    Mamm Genome 19:406-12. 2008

Detail Information

Publications11

  1. pmc Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice
    Yanqing Gong
    Joseph J Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195, USA
    J Clin Invest 118:3012-24. 2008
    ..Thus, targeting the Plg/MMP-9 pathway may be an attractive approach to regulate inflammatory responses and AAA development...
  2. pmc Genetic dissection of quantitative trait Loci for hemostasis and thrombosis on mouse chromosomes 11 and 5 using congenic and subcongenic strains
    Jane Hoover-Plow
    Department of Cardiovascular Medicine and Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Clinic, Lerner Research Institute, Cleveland, Ohio, United States of America
    PLoS ONE 8:e77539. 2013
    ..Using congenic and subcongenic analysis, candidate genes previously identified and novel genes were identified as modifiers of hemostasis and thrombosis in each of the loci Hmtb6, Hmtb4, Hmtb10, and Hmtb11. ..
  3. pmc Lipoprotein(a) metabolism: potential sites for therapeutic targets
    Jane Hoover-Plow
    J J Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44139, USA
    Metabolism 62:479-91. 2013
    ..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...
  4. pmc Challenges for heart disease stem cell therapy
    Jane Hoover-Plow
    Departmentof Cardiovascular Medicine, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
    Vasc Health Risk Manag 8:99-113. 2012
    ..This review is an overview of stem cell therapy for CVD and discusses the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress...
  5. pmc Plasminogen regulates stromal cell-derived factor-1/CXCR4-mediated hematopoietic stem cell mobilization by activation of matrix metalloproteinase-9
    Yanqing Gong
    Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
    Arterioscler Thromb Vasc Biol 31:2035-43. 2011
    ..Plasminogen (Plg) has been shown to be critical for HPSC mobilization. Here, we investigated the role of Plg in G-CSF-induced HPSC mobilization and the underlying mechanism...
  6. pmc Mouse chromosome 17 candidate modifier genes for thrombosis
    Qila Sa
    Departments of Cardiovascular Medicine and Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, OH, 44195, USA
    Mamm Genome 21:337-49. 2010
    ..Although other homologous genes in the QTL region cannot be ruled out as causative genes, further investigation of Emilin2 as a candidate gene for thrombosis susceptibility is warranted...
  7. pmc Does plasmin have anticoagulant activity?
    Jane Hoover-Plow
    Joseph J Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiovascular Medicine, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio 44195, USA
    Vasc Health Risk Manag 6:199-205. 2010
    ..However, inactivation of coagulation factors by plasmin may be useful as a localized anticoagulant therapy or as a combined thrombolytic and anticoagulant therapy...
  8. pmc A physiological function for apolipoprotein(a): a natural regulator of the inflammatory response
    Jane Hoover-Plow
    Department of Molecular Cardiology, NB50, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Exp Biol Med (Maywood) 234:28-34. 2009
    ..Hence, apo(a) may function as a cell specific suppressor of the inflammatory response...
  9. pmc Strain and model dependent differences in inflammatory cell recruitment in mice
    J L Hoover-Plow
    Department of Cardiovascular Medicine and Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, NB50, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
    Inflamm Res 57:457-63. 2008
    ..The objective of this study was to determine genetic differences in inflammation in these distinct inbred mouse strains...
  10. pmc Quantitative trait locus analysis for hemostasis and thrombosis
    Qila Sa
    Department of Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland, OH 44195, USA
    Mamm Genome 19:406-12. 2008
    ..Thus, we have identified new QTLs and candidate genes not previously known to influence thrombotic risk...
  11. pmc Lp(a)/apo(a) modulate MMP-9 activation and neutrophil cytokines in vivo in inflammation to regulate leukocyte recruitment
    Menggui Huang
    Department of Molecular Cardiology, The Cleveland Clinic Lerner Research Institute, Cleveland, Ohio
    Am J Pathol 184:1503-17. 2014
    ....