title: 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.affiliation: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Sven
authors.initials: S
authors.lastname: Terclavers
authors.forename: Bjorn
authors.initials: B
authors.lastname: Vanwetswinkel
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Andrew
authors.initials: A
authors.lastname: Baker
authors.forename: Desire
authors.initials: D
authors.lastname: Collen
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D018014:Gene Transfer Techniques; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011312:Pressure; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000172:deficiency; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D019715:Tissue Inhibitor of Metalloproteinase-1; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9