An anti-αVβ3 antibody inhibits coronary artery atherosclerosis in diabetic pigs. (March 2017)

• Record Type: Journal Article
• Authors: Maile, L.A.; Busby, W.H.; Xi, G.; Gollahan, K.P.; Flowers, W.; Gafbacik, N.; Gafbacik, S.; Stewart, K.; Merricks, E.P.; Nichols, T.C.; Bellinger, D.A.; Clemmons, D.R.
• Is Part Of: Atherosclerosis. Volume 258(2017)
• Page Start: 40
• Page End: 50
• Publication Date: 2017-03
• Subjects: Insulin-like growth factor-I -- Integrin -- Hyperlipidemia -- Extracellular matrix -- Hyperglycemia; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2017.01.030
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Diabetes is a major risk factor for the development of atherosclerosis. Hyperglycemia stimulates vascular smooth muscle cells (VSMC) to secrete ligands that bind to the αVβ3 integrin, a receptor that regulates VSMC proliferation and migration. This study determined whether an antibody that had previously been shown to block αVβ3 activation and to inhibit VSMC proliferation and migration in vitro, inhibited the development of atherosclerosis in diabetic pigs. Methods: Twenty diabetic pigs were maintained on a high fat diet for 22 weeks. Ten received injections of anti-β3 F(ab)2 and ten received control F(ab)2 for 18 weeks. Results: The active antibody group showed reduction of atherosclerosis of 91 ± 9% in the left main, 71 ± 11%, in left anterior descending, 80 ± 10.2% in circumflex, and 76 ± 25% in right coronary artery, ( p < 0.01 compared to lesions areas from corresponding control treated arteries). There were significant reductions in both cell number and extracellular matrix. Histologic analysis showed neointimal hyperplasia with macrophage infiltration, calcifications and cholesterol clefts. Antibody treatment significantly reduced number of macrophages contained within lesions, suggesting that this change contributed to the decrease in lesion cellularity. Analysis of the biochemical changes within the femoral arteries that received the active antibody showed a 46 ± 12% ( p < 0.05) reduction in the tyrosine phosphorylation of the β3 subunit of αVβ3 and a 40 ± 14% ( p < 0.05) reduction in MAP kinase activation. Conclusions: Blocking ligand binding to the αVβ3 integrin inhibits its activation and attenuates increased VSMC proliferation that is induced by chronic hyperglycemia. These changes result in significant decreases in atherosclerotic lesion size in the coronary arteries. The results suggest that this approach may have efficacy in treating the proliferative phase of atherosclerosis in patients with diabetes. Highlights: Insulin deficient diabetic pigs fed a high cholesterol diet for 20 weeks developed extensive coronary atherosclerosis. Hyperglycemia stimulates secretion of extracellular matrix proteins that bind αVβ3. This activates αVβ3 in diabetic animals. Injection of an antibody against a specific epitope in the β subunit of αVβ3 inhibited atherosclerotic lesion development. The antibody also inhibited macrophage infiltration into lesions as well as MAP kinase activation and cell proliferation. Inhibition of αVβ3 offers a potential therapy for inhibition of atherosclerotic lesion development in patients with diabetes.