Abstract 464: Knockout of Insulin-like Growth Factor-1 Receptor in Monocyte/Macrophage Promotes Atherosclerosis and Induces an Unstable Plaque Phenotype
We have previously shown that infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and anti-oxidant effects and reduces atherosclerotic burden in apolipoprotein E deficient (Apoe-/-) mice. Monocytes/macrophages play a pivotal role in atherogenesis and express high levels of IGF-1 receptor (IGF-1R); however the potential effects of IGF-1 on their function are unknown. Thus, we created monocyte/macrophage specific IGF-1R knockout mice (MΦIgf1rKO) by crossing Igf1r floxed mice with Lysozyme-Cre mice, both on Apoe-/- background, and evaluated atherosclerosis by feeding a high fat diet for 8 wks. MΦIgf1rKO mice had a marked increase in atherosclerotic burden; 41± 12 % and 57 ± 15 % increase in plaque size by en face and cross-section analysis respectively, compared to Igf1r floxed mice (control; n=8, p<0.05). Plaque composition in the aortic root was also substantially altered; MΦIgf1rKO had increased monocyte/macrophage content (anti-Mac3 staining, MΦIgf1rKO, 31 ± 3 % vs. Igf1r floxed, 23 ± 4 %) and a decrease in smooth muscle cell content (anti-α-smooth muscle actin staining, MΦIgf1rKO, 15 ± 4 % vs. Igf1r floxed, 23 ± 3 %), whilst there was no significant change in levels of circulating Ly-6Chi monocyte subpopulation. These changes in composition are consistent with a more inflammatory and less stable plaque phenotype. In fact, the frequency of intraplaque hemorrhage and elastin layer breaks (signs of plaque vulnerability) was higher in MΦIgf1rKO mice (5 in 8 mice positive) than in Igf1r floxed mice (2 in 8 positive). Gene expression analysis in aorta showed that MΦIgf1rKO downregulated TGFβ receptor 1 and 2 (by 37±12 % and 36±10 %, P<0.05, n=10), thrombospondin-1 (by 50±14 %, P<0.01, n=10), LXRβ (by 33±9 %, P<0.01, n=10), RXRα (by 38±11 %, P<0.01, n=10), and ABCA1 and ABCG1 (by 32±14 % and 45±19 %, P<0.05, n=10), and upregulated ACAT-1 (by 58±16 %, P<0.05, n=10) and DGAT-2 (by 115±55 %, P<0.05, n=10). These changes are consistent with decreased SMC content and increased lipid accumulation in macrophages. Taken together, our data indicate that monocyte/macrophage IGF-1R signaling suppresses macrophage accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts its anti-atherogenic effects.
- © 2013 by American Heart Association, Inc.