Blocking Very Late Antigen-4 Integrin Decreases Leukocyte Entry and Fatty Streak Formation in Mice Fed an Atherogenic Diet

• Published in: Circulation research 1999-02, Vol.84 (3), p.345-351
• Main Authors: Shih, Peggy T, Brennan, Marie-Luise, Vora, Devendra K, Territo, Mary C, Strahl, Dana, Elices, Mariano J, Lusis, Aldons J, Berliner, Judith A
• Format: Article
• Language: English
• Subjects: Animals; Aorta - metabolism; Arteriosclerosis - prevention & control; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Female; Fibronectins - physiology; Humans; Integrin alpha4beta1; Integrins - physiology; Leukocytes - physiology; Lipid Metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Rabbits; Receptors, LDL - genetics; Receptors, LDL - physiology; Receptors, Lymphocyte Homing - physiology; Vascular Cell Adhesion Molecule-1 - physiology
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.84.3.345

Atherosclerotic lesion development is characterized by the recruitment of leukocytes, principally monocytes, to the vessel wall. Considerable interest has been focused on the adhesion molecule(s) involved in leukocyte/endothelial interactions. The goal of the present study was to determine the role of the very late antigen-4 (VLA-4) integrin/ligand interaction in fatty streak development using murine models. Because alpha 4 null mice are not viable, a peptidomimetic was used to block VLA-4-mediated leukocyte binding. The ability of a synthetic peptidomimetic of connecting segment-1 (CS-1 peptide) to block the recruitment of leukocytes and the accumulation of lipid in the aortic sinus of either wild-type mice (strain C57BL/6J) or mice with a low-density lipoprotein null mutation (LDLR-/-) maintained on an atherogenic diet was assessed. The active (Ac) CS-1 peptide or scrambled (Sc) CS-1 peptide was delivered subcutaneously into mice using a mini osmotic pump. Mice were exposed to the peptide for 24 to 36 hours before the onset of the atherogenic diet. In C57BL/6J mice, leukocyte entry into the aortic sinus, as assessed by en face preparations, was inhibited by the active peptide (Ac=28 +/- 4, Sc=54 +/- 6 monocytes/valve; P=0.004). Additionally, frozen sections stained with Oil Red O were analyzed to assess lipid accumulation in the aortic sinus. C57BL/6J mice that received the (Ac) compound demonstrated significantly reduced lesion areas as compared with mice that received the (Sc) peptide (Ac=4887 +/- 4438 [micro sign]m, Sc=15 009 +/- 5619 [micro sign]m; P