© 1999 American Heart Association, Inc.
Rapid Communication |
Blocking Very Late Antigen-4 Integrin Decreases Leukocyte Entry and Fatty Streak Formation in Mice Fed an Atherogenic Diet
From UCLA Departments of Pathology (P.T.S., J.A.B.) and Medicine (P.T.S., M.-L.B., D.K.V., M.C.T., A.J.L., J.A.B.), Los Angeles, Calif; Cytel Corporation (D.S., M.J.E.), San Diego, Calif.
Correspondence to Peggy Shih, Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Center for the Health Sciences, 10833 Le Conte Ave, Los Angeles, CA 90095-1732.
Abstract—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 
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
µm2, Sc=15 009 ±5619 µm2;
P<0.0001). In a separate study, LDLR-/- mice were
implanted with pumps containing either the (Ac) or (Sc) peptide before
initiation of the atherogenic diet. Because LDLR-/- mice fed a chow
diet displayed small lesions at 14 weeks, the effects of the peptide
seen in these animals represented a change in early lipid
accumulation rather than initiation. By using whole-mount preparations,
the (Ac) but not the (Sc) peptide significantly reduced the area of
lipid accumulation in the aortic sinus, resulting in an approximate
66% decrease. Plasma analysis from all studies revealed
concentrations of peptide to be present at levels previously
determined by in vitro analysis to block adhesion. (Ac) CS-1
peptide, which blocks VLA-4 on the leukocyte surface, is effective in
reducing leukocyte recruitment and lipid accumulation in the aortic
sinus. The present study provides in vivo evidence that the VLA-4
integrin plays an important role in the initiation of the
atherosclerotic lesion and lipid accumulation, and it suggests a
potential therapeutic strategy for this disease.
Key Words: atherosclerosis • monocyte • connecting segment-1 • fibronectin • 4ß1
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