Abstract 12403: Membrane Type-1 Matrix Metalloproteinase Activity and in vivo Abundance Using Targeted Microbubble Imaging, Intensify During Thoracic Aortic Aneurysm Formation: Relationship to Change in Aortic Diameter
Background: Thoracic aortic aneurysms (TAAs) form in response to enhanced proteolytic activity within the aortic extracellular matrix. Membrane type-1 matrix metalloproteinase (MT1-MMP) is the prototypical membrane bound MMP and plays a multifunctional role in tissue remodeling. However, the relationship between MT1-MMP localization, activation, and aortic expansion remains undefined. Accordingly, the present study tested the hypothesis that MT1-MMP is elevated within the aortic wall during TAA development, and that enhanced activity is associated with aortic expansion and growth.
Methods: Descending thoracic aortas were harvested from C57BL/6J mice at multiple time-points (2-, 4-, 8-, and 16- weeks, n=10 each) post-TAA induction (0.5M calcium chloride, 15 min). MT1-MMP abundance and localization (8-week TAAs (n=6) versus non-TAA controls (n=3)) was determined in vivo by micro-ultrasound imaging with an MT1-MMP-targeted microbubble contrast agent. MT1-MMP activity was assessed by quenched fluorogenic peptide assay and compared to non-TAA control animals (n=10), and the relationship between activity and aortic diameter was determined.
Results: Aortic diameter was increased 72±7% over baseline at 16-weeks (p<0.05) post-TAA induction. MT1-MMP-targeted contrast binding was elevated in 8-week TAAs versus control animals (217±53% vs. 81±8%, p<0.05). MT1-MMP activity was elevated during TAA and demonstrated a significant relationship (r=0.4142, p=0.0205) with the time-dependent change in aortic diameter.
Conclusions: The unique findings from this study demonstrate increased MT1-MMP binding within the thoracic aorta of mice in vivo, 8-wks following TAA induction. Moreover, a significant relationship between MT1-MMP activity and aortic expansion was identified. Together, these results suggest that MT1-MMP may play a mechanistic role in TAA formation and progression.
- © 2010 by American Heart Association, Inc.