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

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 BorgersD Collen, M J Daemen, P Carmeliet^*

^*Corresponding author for this work

CARIM - Cardiovascular Research Institute Maastricht

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1135-42
Number of pages	8
Journal	Nature Medicine
Volume	5
Issue number	10
DOIs	https://doi.org/10.1038/13459
Publication status	Published - Oct 1999

Keywords

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

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10.1038/13459

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Heymans, S., Luttun, A., Nuyens, D., Theilmeier, G., Creemers, E., Moons, L., Dyspersin, G. D., Cleutjens, J. P., Shipley, M., Angellilo, A., Levi, M., Nübe, O., Baker, A., Keshet, E., Lupu, F., Herbert, J. M., Smits, J. F., Shapiro, S. D., Baes, M., ... Carmeliet, P. (1999). Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nature Medicine, 5(10), 1135-42. https://doi.org/10.1038/13459

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

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.",

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

author = "S Heymans and A Luttun and D Nuyens and G Theilmeier and E Creemers and L Moons and Dyspersin, \{G D\} and Cleutjens, \{J P\} and M Shipley and A Angellilo and M Levi and O N{\"u}be and A Baker and E Keshet and F Lupu and Herbert, \{J M\} and Smits, \{J F\} and Shapiro, \{S D\} and M Baes and M Borgers and D Collen and Daemen, \{M J\} and P Carmeliet",

year = "1999",

month = oct,

doi = "10.1038/13459",

language = "English",

volume = "5",

pages = "1135--42",

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Heymans, S, Luttun, A, Nuyens, D, Theilmeier, G, Creemers, E, Moons, L, Dyspersin, GD, Cleutjens, JP, Shipley, M, Angellilo, A, Levi, M, Nübe, O, Baker, A, Keshet, E, Lupu, F, Herbert, JM, Smits, JF, Shapiro, SD, Baes, M, Borgers, M, Collen, D, Daemen, MJ & Carmeliet, P 1999, 'Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure', Nature Medicine, vol. 5, no. 10, pp. 1135-42. https://doi.org/10.1038/13459

TY - JOUR

T1 - Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure

AU - Heymans, S

AU - Luttun, A

AU - Nuyens, D

AU - Theilmeier, G

AU - Creemers, E

AU - Moons, L

AU - Dyspersin, G D

AU - Cleutjens, J P

AU - Shipley, M

AU - Angellilo, A

AU - Levi, M

AU - Nübe, O

AU - Baker, A

AU - Keshet, E

AU - Lupu, F

AU - Herbert, J M

AU - Smits, J F

AU - Shapiro, S D

AU - Baes, M

AU - Borgers, M

AU - Collen, D

AU - Daemen, M J

AU - Carmeliet, P

PY - 1999/10

Y1 - 1999/10

N2 - 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.

AB - 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.

KW - Animals

KW - Arrhythmias, Cardiac

KW - Bone Marrow Transplantation

KW - Cardiac Output, Low/etiology

KW - Cell Movement

KW - Collagenases/metabolism

KW - Gene Transfer Techniques

KW - Heart Rupture/etiology

KW - Leukocytes/cytology

KW - Matrix Metalloproteinase 3/genetics

KW - Matrix Metalloproteinase 9

KW - Metalloendopeptidases/antagonists & inhibitors

KW - Mice

KW - Mice, Mutant Strains

KW - Myocardial Infarction/complications

KW - Neovascularization, Physiologic/drug effects

KW - Plasminogen Activator Inhibitor 1/genetics

KW - Plasminogen Activators/genetics

KW - Plasminogen Inactivators/therapeutic use

KW - Protease Inhibitors/therapeutic use

KW - Tissue Inhibitor of Metalloproteinase-1/genetics

U2 - 10.1038/13459

DO - 10.1038/13459

M3 - Article

C2 - 10502816

SN - 1078-8956

VL - 5

SP - 1135

EP - 1142

JO - Nature Medicine

JF - Nature Medicine

IS - 10

ER -

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

Abstract

Keywords

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