Abstract 12406: Latent Transforming Growth Factor-beta Binding Protein-1 is Cleaved by Matrix Metalloproteinase-2 During Thoracic Aortic Aneurysm Development
Objective: Latent transforming growth factor-beta binding protein-1 (LTBP-1) is a large calcium-binding glycoprotein that plays an important role in the targeting and sequestration of transforming growth factor-beta (TGF-beta) in the extracellular matrix (ECM). Recent studies have demonstrated that mutations in ECM proteins that regulate TGF-beta storage and availability result in pathological conditions such as Marfan syndrome, and can drive thoracic aortic aneurysm (TAA) development. Moreover, because cleavage of LTBP-1 by the matrix metalloproteinases (MMPs) can regulate TGF-beta availability, the present study examined the temporal LTBP-1 cleavage activity in aortic homogenates during TAA development.
Methods: Descending TAAs were induced (0.5M CaCl2, 15 min.) in C57BL/6J mice and aortas were harvested at predetermined time-points (2-, 4-, 8-, and 16-wks; n=10 per group). LTBP-1 cleavage activity was measured in aortic homogenates using an MMP-specific LTBP-1 quenched fluorogenic peptide substrate.
Results: (mean ± SEM) were expressed as a percent change of LTBP-1 cleavage activity from aortic homogenates derived from a group of unoperated control mice (n=10, set at 100%). The relationship between MMP abundance (MMP-2, MT1-MMP) and LTBP-1 cleavage activity was determined.
Results: Aortic diameter was increased 72±7% over baseline at 16-wks following TAA induction. LTBP-1 cleavage activity was elevated in the TAA homogenates at 2-, 4-, and 8-wks, and a significant relationship between MMP-2 and LTBP-1 cleavage was identified (r=0.4059, p=0.0235).
Conclusions: The unique findings of this study define LTBP-1 as a substrate for MMP-2 during TAA development in an established murine model. These data suggest that cleavage of LTBP-1 may play an important role in early TAA formation, through the release of TGF-beta from ECM sequestration sites.
- © 2010 by American Heart Association, Inc.