BLOCKADE OF VERY LATE ANTIGEN-4 INTEGRIN BINDING TO FIBRONECTIN WITH CONNECTING SEGMENT-1 PEPTIDE REDUCES ACCELERATED CORONARY ARTERIOPATHYIN RABBIT CARDIAC ALLOGRAFTS
S. Molossi et al., BLOCKADE OF VERY LATE ANTIGEN-4 INTEGRIN BINDING TO FIBRONECTIN WITH CONNECTING SEGMENT-1 PEPTIDE REDUCES ACCELERATED CORONARY ARTERIOPATHYIN RABBIT CARDIAC ALLOGRAFTS, The Journal of clinical investigation, 95(6), 1995, pp. 2601-2610
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.