Abstract 10086: Membrane Type-1 Matrix Metalloproteinase Activity and Specific In Vivo Quantitation Using Specific Targeted Microbubble Imaging: Relation to Left Ventricular Remodeling Following Myocardial Infarction
Background: Membrane type-1 matrix metalloproteinase (MT1-MMP) is increased in humans and animals with left ventricular (LV) remodeling. However, whether and to what degree modulation of MT1-MMP alters MT1-MMP activity and in vivo localization in the context of LV remodeling following myocardial infarction (MI) remains to be defined.
Methods/Results: Following baseline echo measurements of LV ejection fraction (LVEF) and end-diastolic volume (LVEDV), MI was induced in mice with cardiac restricted over-expression of MT1-MMP (MT1-MMPexp; full length human; n=6), reduced MT1-MMP expression (heterozygous; MT1-MMP+/−; n=5), and wild type (WT; n=6) and measurements repeated at 2 weeks. When compared to non-MI WT (n=10), LVEDV (μL) was higher in WT-MI and in MT1-MMPexp (74±2 and 76±3, both p<0.05), but lower than WT-MI and MT-MMPexp MI in the MT1-MMP+/− mice (66±3, p<0.05). MT1-MMP activity (fluorogenic substrate, ng/mg/hr) was higher following MI (138±28 vs 60±3, p<0.05), increased further with MT1-MMPexp (348±28, p<0.05) and was reduced with MT1-MMP+/− (76±4, p<0.05). In vivo localization of MT1-MMP (40 MHz, 30 μm resolution) was performed at 5 min intervals for up to 20 min following tail vein injection of MT1-MMP antibody-conjugated echodense microbubbles (3 μm diameter, 3.6×107 microbubbles) and contrast retention (colored yellow, Figure) was normalized to the area of the myocardium (μm2). In the viable myocardial region, microbubble retention (arrows) was higher than non-MI WT in all MI groups, but was highest in the MT1-MMPexp group (Figure, bottom).
Conclusions: These unique findings demonstrate that, following MI, MT1-MMP abundance is increased in normally perfused myocardium, which can be visualized in vivo using antibody-tagged echocontrast. Further, regulation of MT1-MMP was directly related to microbubble binding and LV dilation post-MI. Thus, MT1-MMP is likely a key proteolytic process and an imaging target following myocardial infarction.
- © 2010 by American Heart Association, Inc.