Abstract 13878: Smooth Muscle-specific IGF-1 Receptor Deficiency Increases Atherosclerosis and Promotes Features of Unstable Plaque
Insulin-like growth factor I (IGF-1) has pleiotropic effects, stimulating growth, differentiation, survival and anabolism, in multiple tissues and cell types including smooth muscle cells (SMC). Although IGF-1 is a SMC mitogen, we have previously shown that systemic IGF-1 infusion reduces
atherosclerosis in Apoe-null mice. To determine the role of SMC IGF-1 receptor (IGF-1R) signaling in atherogenesis, we generated SMC-specific IGF-1R/Apoe-double knockout mice (22KO) by crossing floxed IGF-1R mice (FIR) with mice expressing Cre recombinase under control of the SM22α promoter. 22KO mice had >80% reduction in aortic IGF-1R expression vs. FIR mice, no change in serum IGF-1 levels (22KO: 325.99±24.24 ng/ml vs FIR: 348.11±18.79 ng/ml, P=NS), reduced body weight (15±3% decrease, p<0.05) and weight of SMC-rich organs (urinary bladder, 37±4% decrease; aorta, 18±2% decrease, p<0.05), thinner aortic wall media (40±5% decrease, p<0.05), reduced size of individual aortic SMC (23±3% decrease, P<0.05) without a change in aortic SMC number suggesting that the IGF-1R regulated primarily hypertrophic and not proliferative growth of SMC. 22KO mice had decreased aortic medial and adventitial collagen (12±3% and 38±5% decrease, vs FIR, respectively, Trichrome staining). After 12 weeks on a Western diet 22KO mice had markedly increased aortic plaque area (en face analysis with Oil red staining, 22KO: 26±5%, n=12, vs. FIR: 7±4%, n=16, P<0.01) and increased aortic valve plaque cross-sectional area (22 KO: 39±5%, n=18, vs FIR: 24±3%, n=24, P<0.001). Atherosclerotic plaques in 22KO mice had no change in macrophage infiltration (22 KO: 34±5% vs. FIR: 36±3%, P=NS, Mac-3 staining), larger necrotic cores (22KI: 56±6% vs. FIR: 45±6%, p<0.05), decreased α-smooth muscle actin-positive area (21±3% decrease, p<0.05) and a marked reduction in plaque collagen (22KI: 7±2% vs. FIR: 31±4%, P<0.001) consistent with features of unstable plaque. In summary, SMC-specific IGF-1R deficiency increased atherosclerotic plaque burden and necrotic core size and reduced plaque SMC and collagen content suggesting a more unstable plaque phenotype. These data indicate that SMC-specific IGF-1-dependent signaling plays a critical role in atheroprotective effects of IGF-1.
Author Disclosures: S. Shai: None. S. Sukhanov: Research Grant; Significant; NHLBIR21 grant, PI. Y. Higashi: None. V.J. D’Ambra: None. T.C. Woods: None. P. Delafontaine: None.
- © 2014 by American Heart Association, Inc.