title: The plasminogen-MMP system is more activated in the scar than in viable myocardium 3 months post-MI in the rat.
abstract: Left ventricular (LV) remodeling following myocardial infarction (MI) is a complex process involving extracellular matrix degradation and fibrosis. While early remodeling is beneficial, chronic remodeling leads to decompensated heart failure (HF). We assessed the hypothesis that activation of the plasminogen-MMP system is involved in the remodeling of the infarct scar and compared it to the remaining viable myocardium. MI was induced by coronary artery ligature in 42 male Wistar rats. Three months following surgery, animals were divided into compensated (n=26) or decompensated (n=16) groups and compared to sham-operated rats (n=17). Scar and remaining viable LV myocardium (LVM) were separately analyzed for MMP-2, -7, -9, urokinase type and tissue type plasminogen activator (uPA and tPA) mRNA levels by RT-PCR. Their protein or activity levels, plus those of plasminogen/plasmin, tissue inhibitor of metalloproteinase-1, -2, -4 (TIMP-1, -2, -4) and plasminogen activator inhibitor-1 (PAI-1) were analyzed in tissue conditioned media by Western blot, ELISA and/or zymography. MMP and plasmin proteolytic activities were increased in the scar as compared to paired LVM thus indicating that activation of plasminogen and pro-MMPs is a key event in scar tissue remodeling. MMP and plasminogen activators (uPA, tPA) mRNAs were increased accordingly. Furthermore, inhibitors of the proteolytic enzymes, TIMP-1 and PAI-1 were increased in the scars from failing hearts and LVM thus suggesting a dynamic interplay between proteolysis and its inhibitors. This study shows a high degree of activation of the MMP-plasminogen system and the balance with their inhibitors in the infarcted myocardium, and suggests that this activation participates more to the remodeling of the scar tissue than to the remaining myocardium.
authors.affiliation: Inserm U460, Cardiovascular Remodeling, CHU Xavier Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris cedex 18, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Gaertner
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Jacob
authors.forename: Fabrice
authors.initials: F
authors.lastname: Prunier
authors.forename: Eduardo
authors.initials: E
authors.lastname: Angles-Cano
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mercadier
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
mesh_terms: D000818:Animals; D001835:Body Weight; D002921:Cicatrix / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D010958:Plasminogen; D020782:Matrix Metalloproteinases