Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice

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 (M Phi-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. M Phi-GF1R-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 M Phi-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from M Phi-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.