© 1999 American Heart Association, Inc.
Integrative Physiology |
Reduction in Atherosclerotic Lesion Size in Pigs by 
Vß3 Inhibitors Is Associated With Inhibition of Insulin-Like Growth Factor-I–Mediated Signaling
From the Department of Pathology and Laboratory Medicine (T.C.N., T.d.L.), the Division of Laboratory Animal Medicine (D.A.B.) and the Department of Medicine (T.C.N., B.Z., D.R.C.), University of North Carolina, Chapel Hill, NC; and Monsanto/Searle, Inc, Chesterfield, Mo (G.A.N., W.E.).
Correspondence to David R. Clemmons, Department of Medicine, University of North Carolina, CB No. 7170, Chapel Hill, NC 27599-7170. E-mail dpm{at}med.unc.edu
Abstract—Insulin-like
growth factor-I (IGF-I) is a potent stimulant of smooth muscle cell
(SMC) migration and proliferation and has been implicated in the
development of experimental atherosclerotic lesions. Because optimal
stimulation of SMC in vitro by IGF-I requires ligand occupancy of
Vß3, these studies were conducted to determine whether Vß3
antagonists would result in a change in lesion size and
whether they could alter IGF-I-mediated actions. Clamps were placed on
the carotid and femoral arteries of normal pigs that had been fed a
high-cholesterol diet for 4 weeks. Vß3
inhibitors (SC-69000, SC-65811) (10-6
mol/L) or saline were infused for 2 weeks into the peristenotic
area. Lesion area, the number of SMC layers, and proliferating cell
nuclear antigen positive cells were determined in a 1.2-mm segment of
each artery. Lesion areas were 304 788±113 453 µ2
(saline), compared with 149 799±35 456 µ2 (SC-69000)
(P<0.01). Lesion areas in arteries treated with
SC-64258, a compound that does not bind to Vß3, were
310 284±160 467 µ2, P=not significant.
In a second experiment, lesion areas were 110 391±17 347
µ2 (saline) and 59 533±17 568 µ2
(SC-65811, P<0.001). Neointimal SMC layers
were reduced by SC-65811 from 7.4±4.5 to 3.0±0.4
(P<0.001). To determine whether IGF-I action was
altered, IGF binding protein-5, which is synthesized in response to
IGF-I, was analyzed. IGF-I binding protein-5 mRNA abundance was
reduced by 67±8% in the 6 lesions treated with SRL-69000 compared
with saline controls (P<0.001). We conclude that
Vß3 antagonists block the development of lesions in
pigs that have been induced by a high-cholesterol diet and
stenosis, and the effect of these compounds is associated with
their ability to inhibit IGF-I–mediated signaling.
Key Words: disintegrin • arteriosclerosis • insulin • signal transduction
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