Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.
Graft arteriopathy, a leading cause of cardiac allograft failure, is associated with increased intimal smooth muscle cells, inflammatory cells, and accumulation of extracellular matrix. We hypothesized that cellular fibronectin plays a pivotal role in the progression of the allograft arteriopathy by directing the transendothelial trafficking of inflammatory cells through interaction of the connecting segment-1 (CS1) motif with the very late antigen-4 (VLA-4) integrin, and tested this in vivo using a blocking peptide. Cholesterol-fed rabbits underwent heterotopic cardiac transplantation without immunosuppression. The treatment group (n = 7) received a synthetic CS1 peptide (1 mg/kg per d, subcutaneously), and the controls (n = 7) received an inactive peptide (1 mg/kg per d, subcutaneously). At 7-8 d after transplantation, hearts were harvested and sectioned for morphometric analysis and immunohistochemical studies. We observed a > 50% decrease in the incidence (P < 0.001) and severity (P < 0.001) of donor coronary artery intimal thickening in the CS1-treated compared with the control group. These findings correlated with reduced infiltration of T cells (P < 0.05), a trend toward decreased expression of adhesion molecules (P < 0.06), and less accumulation of fibronectin (P < 0.03). Our data suggest that the VLA-4-fibronectin interaction is critical to the progression of the allograft arteriopathy by perpetuating the immune-inflammatory response in the vessel wall.
Molossi
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S
Department of Pediatrics, University of Toronto, Ontario, Canada.
Elices
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Arrhenius
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Diaz
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Coulber
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Rabinovitch
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D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003327:Coronary Disease / Q000517:prevention & control*; D004036:Diet, Atherogenic; D005260:Female; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D016027:Heart Transplantation / Q000379:methods*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000166:cytology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011817:Rabbits; D016029:Receptors, Very Late Antigen / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D005353:Fibronectins; D000949:Histocompatibility Antigens Class II; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D010455:Peptides; D016029:Receptors, Very Late Antigen; D019010:Vascular Cell Adhesion Molecule-1; C076687:CS1 peptide; D018799:Intercellular Adhesion Molecule-1