Reduction in Atherosclerotic Lesion Size in Pigs by &agr;V&bgr;3 Inhibitors Is Associated With Inhibition of Insulin-Like Growth Factor-I–Mediated Signaling
作者:
Timothy Nichols,
Tracey Laney,
Bo Zheng,
Dwight Bellinger,
G. Nickols,
Wayne Engleman,
David Clemmons,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 1999)
卷期:
Volume 85,
issue 11
页码: 1040-1040
ISSN:0009-7330
年代: 1999
出版商: OVID
关键词: disintegrin;arteriosclerosis;insulin;signal transduction
数据来源: OVID
摘要:
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 &agr;V&bgr;3, these studies were conducted to determine whether &agr;V&bgr;3 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. &agr;V&bgr;3 inhibitors (SC-69000, SC-65811) (10−6mol/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 &mgr;2(saline), compared with 149 799±35 456 &mgr;2(SC-69000) (P<0.01). Lesion areas in arteries treated with SC-64258, a compound that does not bind to &agr;V&bgr;3, were 310 284±160 467 &mgr;2,P=not significant. In a second experiment, lesion areas were 110 391±17 347 &mgr;2(saline) and 59 533±17 568 &mgr;2(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 &agr;V&bgr;3 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.
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