Abstract 10717: Monocyte/Macrophage Specific Knockout of Insulin-like Growth Factor-1 Receptor Promotes Atherosclerosis and Induces an Unstable Plaque Phenotype
We have previously shown that systemic 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 express high levels of IGF-1 receptor (IGF-1R) and play a pivotal role in atherogenesis but the potential effects of IGF-1 on their function are unknown. To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/macrophage specific IGF-1R knockout mice (MΦIgf1rKO) by crossing Igf1r floxed mice with Lysozyme-Cre recombinase mice, both on Apoe-/- background. MΦIgf1rKO and Igf1r floxed (control) mice were fed a high fat diet for 8 wks, and atherosclerotic burden was measured by Oil red O staining of en face aortae and aortic root cross-section; plaque stability was assessed by modified Carstair’s and Verhoeff-Van Gieson staining of brachiocephalic artery cross-sections. MΦIgf1rKO mice had a marked increase in atherosclerotic burden; 40.5 ± 12.0 % and 57.0 ± 14.9 % increase in plaque size by en face and cross-section analysis respectively compared to Igf1r floxed mice (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 ± 2.8 % vs. Igf1r floxed, 22.5 ± 4.2 %) and a decrease in smooth muscle cell content (anti-α-smooth muscle actin staining, MΦIgf1rKO, 15.3 ± 4.0 % vs. Igf1r floxed, 23.2 ± 2.7 %), consistent with a more inflammatory and less stable plaque phenotype. Moreover, the frequency of intraplaque hemorrhage and elastin layer breaks (signs of plaque vulnerability) was higher in MΦIgf1rKO mice (5 in 6 mice positive) than in Igf1r floxed mice (2 in 6 positive). In cultured macrophages IGF-1 suppressed oxidized LDL induced increase in 12/15-lipoxygenase activity (95 % decrease), lipid internalization and foam cell formation. Taken together, our data indicate that monocyte/macrophage IGF-1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts its anti-atherogenic effects.
- © 2011 by American Heart Association, Inc.