Published online before print April 27, 2001, doi: 10.1161/hh0901.090305
© 2001 American Heart Association, Inc.
Molecular Medicine |
Defect in Insulin-Like Growth Factor-1 Survival Mechanism in Atherosclerotic Plaque–Derived Vascular Smooth Muscle Cells Is Mediated by Reduced Surface Binding and Signaling
From the Departments of Medicine (V.A.P., Q.-J.Z., M.A.S., P.L.W., M.R.B.) and Clinical Biochemistry (K.S., M.A.S.), Addenbrooke’s Hospital, Cambridge, UK; and Department of Histopathology (M.G.), Papworth Hospital, Cambridge, UK.
Correspondence to Prof Martin Bennett, Division of Cardiovascular Medicine, Addenbrooke’s Centre for Clinical Investigation, Box 110, Addenbrooke’s Hospital, Cambridge Hills Rd, Cambridge CB2 2QQ, UK. E-mail to mrb{at}mole.bio.cam.ac.uk
Abstract—Apoptosis of vascular smooth muscle cells (VSMCs) is increased in atherosclerosis compared with normal vessels, where it may contribute to plaque rupture. We have previously found that human plaque–derived VSMCs (pVSMCs) are intrinsically sensitive to apoptosis and not responsive to the protective effects of insulin-like growth factor-1 (IGF-1). We therefore examined the mechanism underlying this defect. Human pVSMCs showed <25% 125I–IGF-1 surface binding, <20% IGF-1 receptor (IGF-1R) expression than that of normal medial VSMCs, and <40% Akt kinase activity in response to IGF-1. pVSMCs expressed and secreted high levels of IGF-1 binding proteins (IGFBPs), and the IGF-1 analogues, long R3 and Des 1,3 IGF-1, which do not bind to IGFBPs, were able to increase pVSMC survival to normal medial VSMC levels. The long R3 survival effect was phosphatidylinositol 3-kinase–mediated, but it was not dependent on Akt activity alone. Intimal pVSMCs in vivo showed reduced IGF-1R expression compared with medial VSMCs, in particular at the shoulder regions of plaques. We conclude that human pVSMCs show an intrinsic sensitivity to apoptosis caused in part by defective expression of IGF-1R, impaired IGF-1–mediated survival signaling and increased IGFBP secretion. This impaired IGF-1 protection against apoptosis may promote VSMC loss and plaque instability in atherosclerosis.
Key Words: apoptosis • atherosclerosis • Akt • plaque rupture • insulin-like growth factor-1 signaling
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