title: Regulation of matrix metalloproteinases and plasminogen activator inhibitor-1 synthesis by plasminogen in cultured human vascular smooth muscle cells.
abstract: Plasmin and matrix metalloproteinases (MMPs) both participate in extracellular matrix remodeling. This study examined the effects of tumor necrosis factor-alpha (TNF-alpha) and plasminogen on collagenase, stromelysin, and plasminogen activator inhibitor-1 (PAI-1) synthesis of collagenase and stromelysin, which remained predominantly in proenzyme forms, as determined by Western analysis of culture media. In contrast, plasminogen and plasmin not only increased secretion of MMPs but also induced cleavage to their active forms. The serine protease inhibitor aprotinin inhibited this activation of MMPs by plasminogen and plasmin. TNF-alpha reduced plasminogen-induced activation of MMPs, suggesting induction of an inhibitor or plasmin generation, such as PAI-1. Enzyme-linked immunosorbent assay of culture media showed that TNF-alpha (10 ng/mL) increased PAI-1 secretion by 4.2 fold compared with control (105.5 +/- 9.6) versus 24.9 +/- 1.7 ng/mL, n = 3). Surprisingly plasminogen also increased PAI-1 secretion by vascular SMCs (3.6-fold over control). These results demonstrate coordination of cytokines and serine proteases in regulating MMP secretion and activation. In addition, the induction of PAI-1 by TNF-alpha and plasminogen suggests a negative feedback mechanisms limit both plasmin-mediated and MMP-mediated matrix degradation.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Cambridge, Mass, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.forename: D E
authors.initials: DE
authors.lastname: Vaughan
authors.forename: S H
authors.initials: SH
authors.lastname: Parikh
authors.forename: A J
authors.initials: AJ
authors.lastname: Grodzinsky
authors.forename: P
authors.initials: P
authors.lastname: Libby
authors.forename: M W
authors.initials: MW
authors.lastname: Lark
authors.forename: R T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D004790:Enzyme Induction; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010958:Plasminogen / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; D010958:Plasminogen; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3