Abstract 8089: A Novel Method to Inhibit Diabetes Accelerated Atherosclerosis in a Pig Model

Abstract

Smooth muscle cells grown in high glucose are more responsive to IGF-I than those grown in normal glucose. This requires ligand binding to a unique region of the β3 subunit (C-loop) of αVβ3 integrin. This study was undertaken to determine whether systemic administration of an anti-C-loop β3 (Cloop) antibody to hyperglycemic pigs would inhibit the IGF-I mediated signaling events and the development of atherosclerosis. Pigs were placed on a high fat diet containing between 0.5 and 2% cholesterol to maintain circulating cholesterol levels > 500mg/dL. Hyperglycemia (glucose levels > 350mg/dL) was induced with a single injection of streptozotocin (50mg/kg). At the onset of hyperglycemia subcutaneous injections of either control or Cloop antibody were given every 72 hours for 16 weeks (0.3mg/kg). The mean neointimal area (defined as the area inside the internal elastic lamina minus the luminal area) of the aorta was reduced by 70% in the pigs treated with the anti-Cloop antibody compared with the diabetic pigs treated with control antibody. There was a > 90% reduction in neointimal area in the left main artery in the treated compared with the untreated control pigs. Similarly, there was a greater than 75% reduction in neointimal area in the right coronary artery and circumflex artery. Treatment with the antibody reduced the neointimal formation in the left anterior descending artery by 30%. Biochemical analysis of femoral artery homogenates demonstrated that treatment with the anti-Cloop antibody reduced MAPK and AKT signaling by 36 and 40 % respectively compared with control treated animals. We have previously shown that IGF-I stimulation of these pathways is increased in hyperglycemia in a β3 ligand occupancy dependent manner and results in SMC migration and proliferation. To confirm inhibition of β3 activation we determined that there was a 43% reduction in β3 phosphorylation, a marker of its activation state. Our results demonstrate that systemic administration of the C-loop antibody to hyperglycemic hyperlipidemic pigs reduces IGF-I signaling and this is associated with a significant reduction in the development of atherosclerotic lesions in the coronary arteries and aorta.