Abstract 17104: Smooth Muscle Protein 22 alpha Promoter-driven Insulin-like Growth Factor I (IGF-1) Receptor Deficiency Increases Atherosclerosis and Promotes Atherosclerotic Plaque Destabilization
We have previously shown that IGF-1 reduces atherosclerosis in Apoe-null mice. We have now generated Apoe-null mice with SM22a promoter-driven IGF-1 receptor (IGF-1R) deficiency (22KI mice). IGF-1R was decreased in both adventitia-free aortas (>80% decrease, P<0.05) and in adventitia in 22KI mice, and also in aortic smooth muscle cells (SMC), embryonic, skin and lung fibroblasts (FB) isolated from 22KI mice indicating that IGF-1R was targeted in both SMC and FB. 22KI mice had decreased for 15±3% body weight and reduced size of aortic medial SMC and adventitial FB (23±3% and 18±3% decrease, respectively, both P<0.05) suggesting that growth retardation was mediated by SMC and FB hypotrophy. 22KI mice had increased atherosclerotic burden in whole aorta preparations (En face analysis, 22KI: 26±5% vs. FIR: 7±4%, P<0.001) and in aortic valve ( H&E-stained cross-sections, 22KI: 39±5% vs. FIR: 24±3%, P<0.05). 22KI mice had reduced collagen in plaques (Trichrome staining, 22KI: 7±2% vs. FIR: 31±4%, P<0.05) and >80% decrease (P<0.05) in the aortic levels of LARP6, collagen mRNA-binding protein. Plaques in 22KI mice had a larger necrotic core, reduced SMC levels (IHC, decreased signal for: a-SMA, 70±3%; calponin, 76±3% and SMMHC, 77±3%, all are SMC markers, P<0.001), reduced SMC proliferation (EdU injection: 72% decrease, P<0.005) and increased SMC apoptosis (TUNEL/a-SMA assay: 2.5-fold increase, P<0.01) suggesting that IGF1R deficiency results in an unstable plaque phenotype. Consistent with that, 22KI mouse had the larger presence of intraplaque hemorrhage, medial elastin breaks and fibrin deposition in plaques in brachiocephalic arteries. Aortic SMC isolated from 22KI mice had reduced proliferation (Edu assay), and suppressed cell migration (wound healing assay) and these effects correlated with complete inhibition of IGF-1-induced PI3 kinase/Akt-dependent signaling (pAkt Ser473 immunoblotting). In summary, SM22a promoter-driven IGF-1R deficiency increases atherosclerosis and promotes an unstable plaque phenotype. Downregulation of LARP6 and disruption in IGF-1-induced Akt signaling might have contributed to the pro-atherogenic phenotype in 22KI mice. These data establishes the importance of IGF-1 signaling in atheroprotection.
Author Disclosures: S. Sukhanov: None. Y. Higashi: None. S. Shai: None. P. Snarski: None. X. Hou: None. S. Danchuk: None. B. Chandrasekar: None. P. Delafontaine: Research Grant; Modest; NIH.
- © 2016 by American Heart Association, Inc.