C. Liao

526 Targeted Delivery of MicroRNA-126 Improves Perfusion in Chronic Hindlimb Ischemia

were treated with a MMP inhibitor, doxycycline, post-surgery. Doxycycline prevented the reduction in plaque size in the AVF group (p 0.05). Plaque MMP-9 expression was increased in AVF vs. control and sham (10.8% 1.4, 3.9% 0.7, 4.6% 1.1, respectively; p 0.0001). MMP-3 expression was increased in AVF vs. control (9.5% 1.5, 5.0% 0.8, respectively; p 0.05). MMP-2 expression was decreased in AVF vs. sham (5.7% 0.5, 11.3% 1.6, respectively; p 0.05). In addition, we overexpressed the tissue inhibitor of metalloproteinase (TIMP-1) in mice before surgery. The increased Timp-1 prevented the reduction in plaque size in the AVF group (p 0.05). All groups had comparable body weight, blood pressure, lipid levels and hematological parameters. There was also no difference in smooth muscle cell and collagen content between groups. To further understand the role of MMPs, we devised an endothelial cell (EC)-macrophage co-culture system where the ECs were exposed to high (15 dynes/cm) or low (0.5 dynes/cm) shear stress. Macrophage migration exposed to EC effluent was performed using a scratch assay. There was a 2.6 fold increase in migration in the high flow condition compared to the low (p 0.05). When the cells were exposed to the MMP inhibitor drug, GM6001, migration was decreased 2 fold (p 0.05). CONCLUSION: Our findings suggest that MMPs play a role in shear stress inducedplaque regression. Shear stress acting on ECs may influence the cells within the plaque by increasing MMP expression allowing for better macrophage mobility and egress which are characteristics of regressing plaques.