title: An anti-αVβ3 antibody inhibits coronary artery atherosclerosis in diabetic pigs.
abstract: 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.
  
  
  
  Twenty diabetic pigs were maintained on a high fat diet for 22 weeks. Ten received injections of anti-β3 F(ab)2and ten received control F(ab)2for 18 weeks.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Maile
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Busby
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xi
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Gollahan
authors.affiliation: Department of Animal Science, NC State University, Raleigh, NC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Flowers
authors.affiliation: Department of Animal Science, NC State University, Raleigh, NC, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gafbacik
authors.affiliation: Department of Animal Science, NC State University, Raleigh, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gafbacik
authors.affiliation: Department of Animal Science, NC State University, Raleigh, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Stewart
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: E P
authors.initials: EP
authors.lastname: Merricks
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Nichols
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Bellinger
authors.affiliation: Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA. Electronic address: endo@med.unc.edu.
authors.forename: D R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058426:Neointima; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D011485:Protein Binding; D034421:Sus scrofa
chemical_list: D007140:Immunoglobulin Fab Fragments; D039302:Integrin alphaVbeta3; D008024:Ligands
keywords: Extracellular matrix; Hyperglycemia; Hyperlipidemia; Insulin-like growth factor-I; Integrin