title: Plasmin promotes foam cell formation by increasing macrophage catabolism of aggregated low-density lipoprotein.
abstract: OBJECTIVE
  The plasmin/plasminogen system is involved in atherosclerosis. However, the mechanisms by which it stimulates disease are not fully defined. A key event in atherogenesis is the deposition of low-density lipoprotein (LDL) on arterial walls where it is modified, aggregated, and retained. Macrophages are recruited to clear the lipoproteins, and they become foam cells. The goal of this study was to assess the role of plasmin in macrophage uptake of aggregated LDL and foam cell formation.
  
  
  RESULTS
  Plasminogen treatment of macrophages catabolizing aggregated LDL significantly accelerated foam cell formation. Macrophage interaction with aggregated LDL increased the surface expression of urokinase-type plasminogen activator receptor and plasminogen activator activity, resulting in increased ability to generate plasmin at the cell surface. The high local level of plasmin cleaves cell-associated aggregated LDL, allowing a portion of the aggregate to become sequestered in a nearly sealed, yet extracellular, acidic compartment. The low pH in the plasmin-induced compartment allows lysosomal enzymes, delivered via lysosome exocytosis, greater activity, resulting in more efficient cholesteryl ester hydrolysis and delivery of a large cholesterol load to the macrophage, thereby promoting foam cell formation.
  
  
  CONCLUSIONS
  These findings highlight a critical role for plasmin in the catabolism of aggregated LDL by macrophages and provide a new context for considering the atherogenic role of plasmin.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Haka
authors.forename: Inna
authors.initials: I
authors.lastname: Grosheva
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
mesh_terms: D000143:Acids / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D002451:Cell Compartmentation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D005341:Fibrinolysin / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D000143:Acids; D000199:Actins; D008077:Lipoproteins, LDL; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator
keywords: aggregated low-density lipoprotein; atherosclerosis; fibrinolysin; foam cells; low-density lipoprotein cholesterol; macrophages