Nature Medicine
5, 1135 - 1142 (1999)
doi:10.1038/13459
Inhibition of plasminogen activators or matrix metalloproteinases prevents
cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure
S. Heymans1, A. Luttun1, 10, D. Nuyens1, 10, G. Theilmeier1, E. Creemers2, L. Moons1, G.D. Dyspersin3, J.P.M. Cleutjens2, M. Shipley4, A. Angellilo1, M. Levi1, O. Nü e5, A. Baker6, E. Keshet7, F. Lupu8, J-M Herbert1, 9, J.F.M. Smits2, S.D. Shapiro4, M. Baes1, M. Borgers3, D. Collen1, M. J.A.P. Daemen2
& P. Carmeliet11
Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity, Leuven, Belgium
2
Cardiovascular Research Institute, University of Maastricht
, 6200 MD, The Netherlands
3
Janssen Research Foundation, Tumhoutsesteenweg
30, 2340, Beerse, Belgium
4
Departments of Pediatrics, Cell Biology and Medicine,
Washington University School of Medicine, 216 South Kinghighway
Blvd., St. Louis, Missouri, USA
5
Division of Infectious Diseases, University Hospital
Geneva, 24 Rue Mecheli-du-Crest, CH-1211 Geneva
14, Switzerland
6
Departments of Medicine and Therapeutics, Western Infirmary,
44 Church Street, University of Glasgow, Glasgow G11
6NT, United Kingdom
7
Department of Molecular Biology, Hebrew University-Hadassah
Medical School, Jerusalem 91120, Israel
8
Vascular Biology Laboratory, Weston Experimental Research
Center, Thrombosis Research Institute, Emanuel Kaye Building,
Canrcsa Road, Chelsea, London SW3 6LR,
United Kingdom 9
Sanofi Recherche, Haeobiology Research Department,
195 Route d'Espange, 31036 Toulouse Cedex,
France
10
A.L. and D.N. contributed equally to this study
Correspondence should be addressed to P. Carmeliet peter.carmeliet@med.kuleuven.ac.beCardiac 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.
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