title: Inhibition of urokinase-type plasminogen activator or matrix metalloproteinases prevents cardiac injury and dysfunction during viral myocarditis.
abstract: BACKGROUND
  Acute viral myocarditis is an important cause of cardiac failure in young adults for which there is no effective treatment apart from general heart failure therapy. The present study tested the hypothesis that increased expression of the proteinases urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) is implicated in cardiac inflammation, injury, and subsequent failure during Coxsackievirus-B3 (CVB3)-induced myocarditis.
  
  
  RESULTS
  First, we showed increased expression and activity of uPA and MMP-9 in wild-type mice at 7 days of CVB3-induced myocarditis. Targeted deletion of uPA, which resulted in reduced MMP activity and cytokine expression or inhibition of MMPs by adenoviral gene overexpression of tissue inhibitor of metalloproteinases-1, decreased cardiac inflammation and reduced myocardial necrosis at 7 days and decreased cardiac fibrosis at 35 days after CVB3 infection. Importantly, loss of uPA or MMP activity prevented CVB3-induced cardiac dilatation and dysfunction, as determined by serial echocardiography.
  
  
  CONCLUSIONS
  Loss of uPA or MMP activity reduces the cardiac inflammatory response after CVB3 infection, thereby protecting against cardiac injury, dilatation, and failure during CVB3-induced myocarditis.
authors.affiliation: Molecular and Experimental Cardiology, CARIM, Department of Cardiology, P. Debyelaan 25, PO Box 5800, 6202AZ Maastricht, The Netherlands. s.heymans@cardio.unimaas.nl
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauschinger
authors.forename: Armando
authors.initials: A
authors.lastname: De Palma
authors.forename: Angela
authors.initials: A
authors.lastname: Kallwellis-Opara
authors.forename: Susanne
authors.initials: S
authors.lastname: Rutschow
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.forename: Davy
authors.initials: D
authors.lastname: Vanhoutte
authors.forename: Fangye
authors.initials: F
authors.lastname: Gao
authors.forename: Raimund
authors.initials: R
authors.lastname: Torpai
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Padalko
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D000818:Animals; D016207:Cytokines / Q000032:analysis / Q000235:genetics / Q000502:physiology; D004108:Dilatation, Pathologic / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004719:Endomyocardial Fibrosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D029822:Enterovirus B, Human; D004769:Enterovirus Infections / Q000150:complications* / Q000503:physiopathology; D005260:Female; D005341:Fibrinolysin / Q000032:analysis / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006321:Heart / Q000503:physiopathology / Q000821:virology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control* / Q000821:virology*; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology
chemical_list: D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases