Abstract 759: Alterations in Membrane Type-1 Matrix Metalloproteinase Abundance following Induction of Thoracic Aortic Aneurysm in a Murine Model
Thoracic aortic aneurysm (TAA) formation is a multifactorial process resulting from extracellular matrix (ECM) remodeling. The matrix metalloproteinases (MMPs) play a requisite role in TAA production. The membrane-bound MMPs (MT-MMPs), a novel MMP class, serve several biological functions including activation of other MMPs such as MMP-2, growth factor release, and direct ECM degradation. The present study examined MT1-MMP abundance and its regulation with MMP-2 and TIMP-2 during TAA development. 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). Change in aortic diameter was determined by video micrometry at baseline and terminal surgery. MT1-MMP, MMP-2, and TIMP2 expression and abundance were determined by real-time quantitative PCR and immunoblotting, respectively. Results (mean±SEM) are expressed as a percent change from unoperated reference control mice (n=10, set at 100%). Aortic diameter increased over time 172.4±7.2% at 16-wks. MT1-MMP, MMP-2 and TIMP-2 protein levels were increased at all time points post-TAA induction (Figure⇓). In addition, MMP-2 displayed elevated gene expression at 4-wks post-TAA induction (1.66 fold increase, p=0.0490). MT1-MMP and TIMP-2 expression did not change over time. These unique findings demonstrate elevated MT1-MMP protein levels associated with aortic dilatation, and suggest MT1-MMP plays a multifunctional role in TAA development: first by activating preformed pools of MMP-2 at early time points, and later by direct degradation or release of ECM substrates.