An anti-αVβ3 antibody inhibits coronary artery atherosclerosis in diabetic pigs

Autor: Elizabeth P. Merricks, Walker H. Busby, Dwight A. Bellinger, Gang Xi, N. Gafbacik, K.P. Gollahan, W. L. Flowers, Timothy C. Nichols, Laura A. Maile, Kara R Stewart, David R. Clemmons, S. Gafbacik
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
Vascular smooth muscle
Injections
Subcutaneous
Sus scrofa
Coronary Artery Disease
030204 cardiovascular system & hematology
Ligands
Muscle
Smooth
Vascular
Diabetes Mellitus
Experimental
Lesion
Immunoglobulin Fab Fragments
03 medical and health sciences
0302 clinical medicine
Neointima
medicine.artery
Diabetes mellitus
Internal medicine
Hyperlipidemia
medicine
Animals
Phosphorylation
Receptor
Cell Proliferation
biology
business.industry
Macrophages
Integrin alphaVbeta3
medicine.disease
Coronary Vessels
Plaque
Atherosclerotic
Femoral Artery
Coronary arteries
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Right coronary artery
biology.protein
medicine.symptom
Antibody
Cardiology and Cardiovascular Medicine
business
Diabetic Angiopathies
Protein Binding
Zdroj: Atherosclerosis. 258:40-50
ISSN: 0021-9150
Popis: 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)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.
Databáze: OpenAIRE
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