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

Nature Medicine volume 5, pages 1135–1142 (1999)Cite this article

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.

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Figure 1: Myocardial infarction and cardiac rupture.
Figure 2: Infarct healing.
Figure 3: Impaired myocardial healing and cardiac function in u-PA–/– mice.
Figure 4: Abnormal conduction, repolarization and arrhythmias in infarcted u-PA–/– mice.
Figure 5: Increased ischemia in residual viable u-PA–/– myocardium.

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Acknowledgements

The authors thank J.M. Herbert and F. Bono for measurements of TGFβ-1; I. Van Horebeek for help with ATP and lactate measurements; R. Gerard for the AdRR5 and AdPAI-1 adenovirus, M. Van Bilzen, P. Doevedans and M. Palmen; and A. Bouché, M. De Mol, I. Cornelissen, B. Hermans, K. Deroover, A. Manderveld, S. Jansen, A. Vandenhoeck, P. Van Wesemael, S. Wyns and F. Thoné. S.H. is a Fund for Scientific Research. research assistant; G.T. is a recipient of the German Research Foundation.

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Author notes

  1. A. Luttun and D. Nuyens: A.L. and D.N. contributed equally to this study

Authors and Affiliations

  1. Center for Transgene Technology and Gene Therapy, Flanders Interuniversity, Leuven, Belgium

    S. Heymans, A. Luttun, D. Nuyens, G. Theilmeier, L. Moons, A. Angellilo, M. Levi, J-M Herbert, M. Baes, D. Collen & P. Carmeliet

  2. Cardiovascular Research Institute, University of Maastricht , 6200 MD, The Netherlands

    E. Creemers, J.P.M. Cleutjens, J.F.M. Smits & M. J.A.P. Daemen

  3. Janssen Research Foundation, Tumhoutsesteenweg 30, Beerse, 2340, Belgium

    G.D. Dyspersin & M. Borgers

  4. Departments of Pediatrics, Cell Biology and Medicine Washington University School of Medicine, 216 South Kinghighway Blvd., St. Louis, Missouri, USA

    M. Shipley & S.D. Shapiro

  5. Division of Infectious Diseases, University Hospital Geneva, 24 Rue Mecheli-du-Crest, 14, Geneva, CH-1211, Switzerland

    O. Nüβe

  6. Departments of Medicine and Therapeutics, Western Infirmary 44 Church Street, University of Glasgow, Glasgow, G11 6NT, United Kingdom

    A. Baker

  7. Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel

    E. Keshet

  8. Vascular Biology Laboratory, Weston Experimental Research Center, Thrombosis Research Institute, Emanuel Kaye Building, Canrcsa Road, Chelsea, London, SW3 6LR, United Kingdom

    F. Lupu

  9. Haeobiology Research Department, Sanofi Recherche, 195 Route d'Espange, Toulouse Cedex, 31036, France

    J-M Herbert

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Correspondence to P. Carmeliet.

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Heymans, S., Luttun, A., Nuyens, D. et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure . Nat Med 5, 1135–1142 (1999). https://doi.org/10.1038/13459

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