BLOCKADE OF VERY LATE ANTIGEN-4 INTEGRIN BINDING TO FIBRONECTIN WITH CONNECTING SEGMENT-1 PEPTIDE REDUCES ACCELERATED CORONARY ARTERIOPATHYIN RABBIT CARDIAC ALLOGRAFTS

Graft arteriopathy, a leading cause of cardiac allograft failure, is a ssociated with increased intimal smooth muscle cells, inflammatory cel ls, and accumulation of extracellular matrix, We hypothesized that cel lular fibronectin plays a pivotal role in the progression of the allog raft arteriopathy by directing the transendothelial trafficking;of inf lammatory cells through interaction of the connecting segment-1 (CS1) moth with the very late antigen-4 (VLA-4) integrin, and tested this in vivo using a blocking peptide, Cholesterol-fed rabbits underwent hete rotopic cardiac transplantation without immunosuppression, The treatme nt group (n = 7) received a synthetic CS1 peptide (1 mg/kg per d, subc utaneously), and the controls (n = 7) received an inactive peptide (1 mg/kg per d, subcutaneously). At 7-8 d after transplantation, hearts w ere harvested and sectioned for morphometric analysis and immunohistoc hemical studies, We observed a > 50% decrease in the incidence (P < 0. 001) and severity (P < 0.001) of donor coronary artery intimal thicken ing in the CS1-treated compared with the control group, These findings correlated with reduced infiltration of T cells (P < 0.05), a trend t oward 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 allogr aft arteriopathy by perpetuating the immune-inflammatory response in t he vessel wall.