Abstract 3761: A Monoclonal Antibody that Targets a Novel Site on the β3 Subunit of the αVβ3 Integrin Blocks Lesion Development in a Porcine Model of Diabetes Accelerated Atherosclerosis
Smooth muscle cells (SMC) grown in high glucose are more responsive to IGF-I than those grown in normal glucose, suggesting that enhancement of IGF-I actions may contribute to accelerated lesion development observed in patients with diabetes. This enhanced response requires ligand binding to the C-loop region of the β3 subunit of the αVβ3 integrin. We aimed to determine whether administration of an anti-C-loop β3 antibody to hyperglycemic pigs would inhibit the IGF-I mediated signaling events and the development of atherosclerosis. 8 male diabetic pigs were fed a high cholesterol high fat diet for 8 weeks, then, the F(ab)2 of the monoclonal antibody was administered, via Alzet minipump, into one of the femoral arteries while the other artery received vehicle. After 5 months the arteries were removed and sections prepared for lesion analysis or snap frozen, and subsequently homogenized. Morphometric analysis of the arteries showed a 55 ± 8 % reduction in lesion area in the arteries that were treated with the F(ab)2 compared with control arteries. Immunoblotting showed a significant, 75 ± 18 %, reduction in β3 phosphorylation (a marker of β3 activation) in artery homogenates from vessels treated with antibody compared with control. Shc phosphorylation, which is required for IGF-I stimulated SMC migration/proliferation, was significantly reduced by 49 % ± 12 in the treated vessels compared with control. There was also a significant, 79 ± 20 %, reduction in Shc recruitment to SHPS-1, a requisite for Shc phosphorylation. MAPK activation, a marker of downstream signaling, was significantly reduced by 71 ± 19 % in treated vessels compared with control. Our results demonstrate that administration of an antibody raised to the C-loop of the β3 subunit of αVβ3 to hyperglycemic hyperlipidemic pigs reduces IGF-I signaling and this is associated with a significant reduction in the development of atherosclerotic lesions.
This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).