Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure

S Heymans; A Luttun; D Nuyens; G Theilmeier; E Creemers; L Moons; G D Dyspersin; J P Cleutjens; M Shipley; A Angellilo; M Levi; O Nübe; A Baker; E Keshet; F Lupu; J M Herbert; J F Smits; S D Shapiro; M Baes; M Borgers; D Collen; M J Daemen; P Carmeliet

doi:10.1038/13459

Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure

Nat Med. 1999 Oct;5(10):1135-42. doi: 10.1038/13459.

Authors

Affiliation

¹ Center for Transgene Technology, Flanders Interuniversity, Leuven, Belgium.

PMID: 10502816
DOI: 10.1038/13459

Abstract

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arrhythmias, Cardiac
Bone Marrow Transplantation
Cardiac Output, Low / etiology*
Cell Movement
Collagenases / metabolism
Gene Transfer Techniques
Heart Rupture / etiology*
Leukocytes / cytology
Leukocytes / metabolism
Matrix Metalloproteinase 3 / genetics
Matrix Metalloproteinase 9
Metalloendopeptidases / antagonists & inhibitors*
Mice
Mice, Mutant Strains
Myocardial Infarction / complications*
Myocardial Infarction / drug therapy*
Neovascularization, Physiologic / drug effects
Plasminogen Activator Inhibitor 1 / genetics
Plasminogen Activator Inhibitor 1 / metabolism
Plasminogen Activators / genetics
Plasminogen Inactivators / therapeutic use*
Protease Inhibitors / therapeutic use*
Tissue Inhibitor of Metalloproteinase-1 / genetics
Tissue Inhibitor of Metalloproteinase-1 / metabolism

Substances

Plasminogen Activator Inhibitor 1
Plasminogen Inactivators
Protease Inhibitors
Tissue Inhibitor of Metalloproteinase-1
Plasminogen Activators
Collagenases
Metalloendopeptidases
Matrix Metalloproteinase 3
Matrix Metalloproteinase 9