Abstract 15093: Insulin-Like Growth Factor 1 Regulates Lipid Accumulation in Macrophages - A Potential Mechanism for Insulin-Like Growth Factor 1 Mediated Atheroprotection
Lipid accumulation and foam cell formation is a hallmark of atherogenesis, whereas apoptosis of foam cells leads to necrotic core formation and plaque vulnerability. Insulin-like growth factor-1 (IGF-1) is anti-atherogenic, and loss of IGF-1 signaling in macrophages not only increases plaque burden, but also induces a vulnerable plaque phenotype with enlarged necrotic cores and thin fibrous caps. We investigated potential mechanisms for accelerated atherosclerosis in macrophage specific IGF-1R knockout mice (MΦIgf1rKO). MΦIgf1rKO had a marked increase in atherosclerotic burden after 8 wks on a high-fat diet: 41±12 % and 57±15 % increase by en face aorta and aortic sinus cross-section analysis respectively, vs. Igf1r floxed mice (n=8, p<0.05). Plaque composition was substantially altered: MΦIgf1rKO had increased monocyte/macrophage content (Mac3 staining, 39±13 % increase, P<0.05) and a decrease in smooth muscle cell content (α-smooth muscle actin staining, 34±17 % decrease, P<0.05). Aortic gene expression analysis showed that MΦIgf1rKO downregulated ABCA1 and ABCG1 (by 32±14 % and 45±19 %, P<0.05, n=10), transporters responsible for lipid efflux from macrophages, and upregulated ACAT-1 and DGAT-2 (by 58±16 % and 115±55 %, P<0.05, n=10), lipid metabolism enzymes responsible for lipid storage; however MΦIgf1rKO did not alter Msr1, CD36, or LOX-1 expression. Furthermore, macrophage-specific IGF-1R knockout suppressed PPARγ and LXRβ (by 47.6±2.5 % and 43.0±10.8 %, P<0.01), consistent with changes in expression of lipid transport and lipid metabolism related genes, namely, ABCA1, ABCG1, ACAT-1 and DGAT-2. We assessed the effect of IGF-1 on lipid transport and found that IGF-1 potently reduced lipid accumulation (67±5 % reduction, P<0.01) in cultured THP-1 macrophages. Our findings suggest that loss of IGF-1 signaling in macrophages promotes lipid accumulation via a reduction in ABCA1 and ABCG1 leading to reduced lipid efflux, thereby enhancing foam cell formation and necrotic core enlargement, which account for a vulnerable plaque phenotype. IGF-1 regulation of lipid accumulation provides a novel therapeutic strategy to treat atherosclerotic vascular disease and to promote plaque stabilization.
- © 2013 by American Heart Association, Inc.