title: The role of macrophage-derived urokinase plasminogen activator in myocardial infarct repair: urokinase attenuates ventricular remodeling.
abstract: Cardiac plasmin activity is increased following myocardial ischemia. To test the hypothesis that macrophage-derived uPA is a key mediator of repair following myocardial infarction, we performed myocardial infarction on mice with macrophage-specific over-expression of uPA (SR-uPA mice). SR-uPA(+/0) mice and wild-type littermates were sacrificed at 5 days or 4 weeks after infarction and cardiac content of macrophages, collagen, and myofibroblasts was quantified. Cardiac function and dimensions were assessed by echocardiography at baseline and at 4 weeks post-infarction. At 4 weeks after myocardial infarction, macrophage counts were increased in SR-uPA(+/0) mice in the infarct (13.1 vs. 4.9%, P<0.001) and distant uninfarcted regions (5.9 vs. 2.4%, P<0.001). Infarct scar was thicker in SR-uPA(+/0) mice (0.54+/-0.03 mm vs. 0.45+/-0.03 mm, P<0.05) and infarct cardiac collagen content was increased (72.4+/-3.3% vs. 63.0+/-3.6%, P<0.06). Functionally, these changes resulted in mildly improved fractional shortening in SR-uPA(+/0) mice compared to controls (24.6+/-1.68 vs. 19.8+/-1.3%, P=0.03). At 5 days after infarction there was increased collagen content in the scar without increases in macrophages or myofibroblasts. To understand the mechanisms by which macrophage-derived uPA increases collagen, cardiac fibroblasts were treated with macrophage-conditioned medium or plasmin and expression of ColIalpha1 measured by qPCR. Conditioned media from SR-uPA(+/0) or plasmin-treated non-transgenic macrophages but not plasmin alone increased collagen expression in isolated cardiac fibroblasts. We hypothesize that plasmin generation in the heart in response to injury may induce activation of macrophages to a profibrotic phenotype to allow rapid formation of collagenous scar.
authors.affiliation: University of Washington School of Medicine, Division of Cardiology, Seattle, WA 98195, USA.
authors.forename: Elina
authors.initials: E
authors.lastname: Minami
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.forename: Laura
authors.initials: L
authors.lastname: Malchodi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Deem
authors.forename: Kate
authors.initials: K
authors.lastname: Bertko
authors.forename: Jessica
authors.initials: J
authors.lastname: Meznarich
authors.forename: Monja
authors.initials: M
authors.lastname: Dishmon
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.forename: April
authors.initials: A
authors.lastname: Stempien-Otero
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004452:Echocardiography; D005341:Fibrinolysin / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator