Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure.
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.
Heymans
S
S
Center for Transgene Technology, Flanders Interuniversity, Leuven, Belgium.
Luttun
A
A
Nuyens
D
D
Theilmeier
G
G
Creemers
E
E
Moons
L
L
Dyspersin
G D
GD
Cleutjens
J P
JP
Shipley
M
M
Angellilo
A
A
Levi
M
M
Nübe
O
O
Baker
A
A
Keshet
E
E
Lupu
F
F
Herbert
J M
JM
Smits
J F
JF
Shapiro
S D
SD
Baes
M
M
Borgers
M
M
Collen
D
D
Daemen
M J
MJ
Carmeliet
P
P
D000818:Animals; D001145:Arrhythmias, Cardiac; D016026:Bone Marrow Transplantation; D002303:Cardiac Output, Low / Q000209:etiology*; D002465:Cell Movement; D017364:Collagenases / Q000378:metabolism; D018014:Gene Transfer Techniques; D006341:Heart Rupture / Q000209:etiology*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D010960:Plasminogen Activators / Q000235:genetics; D015849:Plasminogen Inactivators / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D010960:Plasminogen Activators; D017364:Collagenases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9