Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice.

Abstract

Left ventricular (LV) hypertrophy is a natural response of the heart to increased pressure loading, but accompanying fibrosis and dilatation may result in irreversible life-threatening heart failure. Matrix metalloproteinases (MMPs) have been invoked in various cardiac diseases, however, direct genetic evidence for a role of the plasminogen activator (PA) and MMP systems in pressure overload-induced LV hypertrophy and in heart failure is lacking. Therefore, the consequences of transverse aortic banding (TAB) were analyzed in mice lacking tissue-type PA (t-PA(-/-)), urokinase-type PA (u-PA(-/-)), or gelatinase-B (MMP-9(-/-)), and in wild-type (WT) mice after adenoviral gene transfer of the PA-inhibitor PAI-1 or the MMP-inhibitor TIMP-1. TAB elevated LV pressure comparably in all genotypes. In WT and t-PA(-/-) mice, cardiomyocyte hypertrophy was associated with myocardial fibrosis, LV dilatation and dysfunction, and pump failure after 7 weeks. In contrast, in u-PA(-/-) mice or in WT mice after PAI-1- and TIMP-1-gene transfer, cardiomyocyte hypertrophy was moderate and only minimally associated with cardiac fibrosis and LV dilatation, resulting in better preservation of pump function. Deficiency of MMP-9 had an intermediate effect. These findings suggest that the use of u-PA- or MMP-inhibitors might preserve cardiac pump function in LV pressure overloading.

• Authors: Stephane Heymans, Florea Lupu, Sven Terclavers, Bjorn Vanwetswinkel, Jean-Marc Herbert, Andrew Baker, Desire Collen, Peter Carmeliet, Lieve Moons
• Journal: The American journal of pathology (Am J Pathol) Vol. 166 Issue 1 Pg. 15-25 (Jan 2005) ISSN: 0002-9440 [Print] United States
• PMID: 15631996 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Matrix Metalloproteinase Inhibitors
• Plasminogen Activator Inhibitor 1
• Tissue Inhibitor of Metalloproteinase-1
• Urokinase-Type Plasminogen Activator
• Matrix Metalloproteinase 9

Topics

• Animals
• Cardiomegaly (genetics, pathology)
• Disease Models, Animal
• Fibrosis
• Gene Transfer Techniques
• Matrix Metalloproteinase 9 (deficiency)
• Matrix Metalloproteinase Inhibitors
• Mice
• Mice, Knockout
• Myocardium (pathology)
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• Pressure
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors, deficiency)
• Ventricular Dysfunction, Left (prevention & control)
• Ventricular Remodeling (physiology)