| First Author | Higashi Y | Year | 2016 |
| Journal | Circulation | Volume | 133 |
| Issue | 23 | Pages | 2263-78 |
| PubMed ID | 27154724 | Mgi Jnum | J:243983 |
| Mgi Id | MGI:5912762 | Doi | 10.1161/CIRCULATIONAHA.116.021805 |
| Citation | Higashi Y, et al. (2016) Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice. Circulation 133(23):2263-78 |
| abstractText | BACKGROUND: We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and antioxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe)-deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis, but the potential effects of IGF-1 on their function are unknown. METHODS AND RESULTS: To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/macrophage-specific IGF1R knockout (MPhi-IGF1R-KO) mice on an Apoe(-/-) background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MPhi-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil Red O staining of en face aortas and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased alpha-smooth muscle actin-positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MPhi-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MPhi-IGF1R-KO mice showed enhanced proinflammatory responses on stimulation by interferon-gamma and oxidized low-density lipoprotein and elevated antioxidant gene expression levels. Moreover, IGF1R-deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux. CONCLUSIONS: Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts antiatherogenic effects. |
