on June 23, 2005
Published online before print June 23, 2005, doi: 10.1161/01.ATV.0000174807.90292.2f
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Submitted on January 14, 2005
Accepted on June 2, 2005
Genetic Deletion or Antibody Blockade of 
1
1 Integrin Induces a More Stable Plaque Phenotype in ApoE-/- Mice
Kitty Schapira ;
From the Department of Pathology (K.S., E.L., A.R., M.D., S.H.), Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands; and Biogen Idec (A.d.F., A.S., H.G., V.K.) and Alnylam Pharmaceuticals (A.d.F., A.S., V.K.), Cambridge, Mass.
* To whom correspondence should be addressed. E-mail: sheen{at}lpat.azm.nl.
Objective--Adhesive interactions between cells and the extracellular matrix play an important role in inflammatory diseases like atherosclerosis. We investigated the role of the collagen-binding integrin 
1
1 in atherosclerosis.
Methods and Results--ApoE-/- mice were 1-deficient or received early and delayed anti-1 antibody treatment. Deficiency in 1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, 1-deficient mice had a reduced macrophage and CD3+ cell content, collagen and smooth muscle cell content increased, lipid core sizes decreased, and cartilaginous metaplasia occurred. Anti-1 antibody treatment reduced the macrophage content in initial plaques after early and delayed treatment, decreased the CD3+ cell content in advanced plaques after delayed treatment, and increased the collagen content in initial and advanced plaques after delayed treatment. Migration assays performed on 1-deficient macrophages on collagen I and IV substrata revealed that 1-deficient cells can migrate on collagen I, but not IV. Anti-1 antibody treatment of ApoE-/- macrophages also inhibited migration of cells on collagen IV.
Conclusions--Our results suggest that 11 integrin is involved in atherosclerosis by mediating the migration of leukocytes to lesions by adhesion to collagen IV. Blocking this integrin reduces atherosclerosis and induces a more stable plaque phenotype.
Key words: atherosclerosis • macrophages • extracellular matrix • collagen • integrin
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