Genetic deletion or antibody blockade of alpha1beta1 integrin induces a stable plaque phenotype in ApoE-/- mice.

Abstract

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 alpha1beta1 in atherosclerosis.

METHODS AND RESULTS:

ApoE-/- mice were alpha1-deficient or received early or delayed anti-alpha1 antibody treatment. Deficiency in alpha1 integrin reduced the area of atherosclerotic plaques and altered plaque composition by reducing inflammation and increasing extracellular matrix. In advanced plaques, alpha1-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-alpha1 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 alpha1-deficient macrophages on collagen I and IV substrata revealed that alpha1-deficient cells can migrate on collagen I, but not IV. Anti-alpha1 antibody treatment of ApoE-/- macrophages also inhibited migration of cells on collagen IV.

CONCLUSIONS:

Our results suggest that alpha1beta1 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 stable plaque phenotype.

• Authors: Kitty Schapira, Esther Lutgens, Antonin de Fougerolles, Andrew Sprague, Anouk Roemen, Humphrey Gardner, Victor Koteliansky, Mat Daemen, Sylvia Heeneman
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 25 Issue 9 Pg. 1917-24 (Sep 2005) ISSN: 1524-4636 [Electronic] United States
• PMID: 15976328 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Apolipoproteins E
• Collagen Type IV
• Integrin alpha1beta1

Topics

• Animals
• Antibodies (pharmacology)
• Apolipoproteins E (genetics)
• Atherosclerosis (genetics, immunology, physiopathology)
• Cell Adhesion (immunology)
• Cell Movement (immunology)
• Collagen Type IV (genetics, metabolism)
• Female
• Gene Deletion
• Gene Expression
• Integrin alpha1beta1 (genetics, immunology, metabolism)
• Leukocytes (cytology, immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Phenotype