Reduction in atherosclerotic lesion size in pigs by alphaVbeta3 inhibitors is associated with inhibition of insulin-like growth factor-I-mediated signaling.
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 alphaVbeta3, these studies were conducted to determine whether alphaVbeta3 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. alphaVbeta3 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 micron(2) (saline), compared with 149 799+/-35 456 micron(2) (SC-69000) (P<0.01). Lesion areas in arteries treated with SC-64258, a compound that does not bind to alphaVbeta3, were 310 284+/-160 467 micron(2), P=not significant. In a second experiment, lesion areas were 110 391+/-17 347 micron(2) (saline) and 59 533+/-17 568 micron(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 alphaVbeta3 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.
Nichols
T C
TC
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7170, USA.
du Laney
T
T
Zheng
B
B
Bellinger
D A
DA
Nickols
G A
GA
Engleman
W
W
Clemmons
D R
DR
D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects; D016893:Carotid Stenosis / Q000188:drug therapy / Q000378:metabolism; D004036:Diet, Atherogenic; D004353:Drug Evaluation, Preclinical; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000096:biosynthesis / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D008297:Male; D015394:Molecular Structure; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine
D000814:Aniline Compounds; D018975:Insulin-Like Growth Factor Binding Protein 5; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D019030:Receptors, Vitronectin; C402423:SC 64258; C402424:SC 65811; C402422:SC 69000; D007334:Insulin-Like Growth Factor I