Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9943483 | The American Journal of Pathology | 2005 | 11 Pages |
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-PAâ/â), urokinase-type PA (u-PAâ/â), or gelatinase-B (MMP-9â/â), 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-PAâ/â mice, cardiomyocyte hypertrophy was associated with myocardial fibrosis, LV dilatation and dysfunction, and pump failure after 7 weeks. In contrast, in u-PAâ/â 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.
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Authors
Stephane Heymans, Florea Lupu, Sven Terclavers, Bjorn Vanwetswinkel, Jean-Marc Herbert, Andrew Baker, Desire Collen, Peter Carmeliet, Lieve Moons,