Abstract 17553: Smooth Muscle Cell-specific Insulin Growth Factor-1 Overexpression In ApoE-null Mice Does Not Alter Atherosclerotic Plaque Burden but Increases Features of Plaque Stability
Growth factors such as insulin-like growth factor-1 (IGF-1) have been thought to promote atherosclerosis progression in part via stimulation of smooth muscle cell (SMC) migration and proliferation. However, unstable human plaques often have a relative paucity of SMC which could contribute to plaque rupture and clinical events. To determine the effect of stimulation of SMC growth on atherosclerotic plaque development we assessed atherosclerosis in ApoE-null mice overexpressing IGF-1 in SMC under control of the smooth muscle α-actin (α-SMA) promoter (SMP8), and ApoE-null mice (control) fed with Western diet for 12 wks. There was no significant difference in atherosclerotic plaque burden in whole aortas (SMP8, 15.4±5% vs ApoE, 15.3±3.2%) and in the aortic valve (SMP8: 42.8 ±13.9% vs ApoE: 37.9±8.1%), and also no difference in plaque macrophage and TNF-α levels (immunohistochemistry). However, SMP8 mice had a marked increase in SMC marker expression in plaques (α-SMA, 123% increase, n=11, P<0.001; SM22α, 93% increase, P<0.01, calponin, 164% increase, P<0.001). Furthermore SMP8 mice had a 35% increase in plaque SMC number (P<0.05), 4.1-fold increase in collagen (Trichrome staining, P<0.01, confirmed by Picrosirius Red staining), 2.4-fold increase in cap thickness (P<0.01) and 36% reduction in necrotic core area (P<0.005) suggesting that SMC-specific IGF-1 overexpression promoted a more stable plaque phenotype. Plaques from SMP8 and ApoE mice were not different in levels of total cell apoptosis (TUNEL staining), SMC apoptosis (α-SMA/TUNEL staining), and SMC proliferation rate (α-SMA/EdU staining) suggesting that the dominant autocrine/paracrine effect of IGF-1 was to induce SMC migration and differentiation. To further study mechanisms, human aortic SMC were treated with IGF-1 (0–100 ng/ml) for 24h. IGF-1 dose-dependently increased expression of α-SMA, SM22α and calponin (P<0.01) and upregulated collagen I and III synthesis (P<0.01). In summary, SMC-specific IGF-1 overexpression in ApoE-null mice does not alter plaque burden but markedly changes plaque phenotype by reducing necrotic cores and increasing SMC content and differentiation. Our findings suggest that stimulation of IGF-1 signaling may improve atherosclerotic plaque stability.
- © 2010 by American Heart Association, Inc.