Abstract 1212: Insulin-like Growth Factor-I Reduces Inflammatory Responses, Suppresses Oxidative Stress and Decreases Atherosclerosis Progression in ApoE-deficient Mice

Atherosclerosis is a chronic inflammatory disease of the vasculature that is responsible for most cardiovascular disease-related death. We have previously shown that expression of insulin-like growth factor-1 (IGF-1) and its receptor is reduced in areas of advanced human plaque staining positive for oxidized LDL suggesting that decreased IGF-1 activity could contribute to disease development and/or progression. To investigate the potential role of IGF-1 in atherogenesis we infused recombinant human IGF-1 (1.5 mg/kg/day) in 8 week old ApoE-deficient mice on a Western diet. IGF-1 infusion (for 12 weeks) doubled circulating IGF-1 levels compared with saline control (665 ± 93 vs. 283 ± 8 ng/ml) but did not change body weight or total cholesterol levels. IGF-1 infused mice had a 27% reduction in atherosclerotic lesion size compared to control (0.259 ± 0.018 mm² vs. 0.356 ± 0.031 mm², P<0.01) as quantified using aortic valve sections. This decrease correlated with a 36% decrease in plaque macrophage infiltration (0.050 ± 0.003 mm² vs. 0.078 ± 0.007 mm², P<0.01; immunostaining with Mac-3 antibody), a 39% reduction in urine 8-isoprostane levels (an index of systemic oxidative stress) (2.0 ± 0.3 vs. 3.3 ± 0.3 ng/mg creatinine, P<0.01) and a marked decrease in aortic superoxides (85% decrease compared to control, P<0.001, DHE-stained frozen sections with/without pretreatment with superoxide scavenger PEG-SOD). IGF-1 reduced aortic mRNA levels of the proinflammatory cytokines IL-6 and TNF-α, by 2.9-fold and 4.2-fold, respectively, without changing serum levels. Furthermore, IGF-1 upregulated aortic eNOS expression by 4.4-fold (real-time PCR) and increased levels of circulating endothelial progenitor cells (EPC) (3.58 ± 0.82 %, IGF-1, vs. 1.61 ± 0.42 %, control, P=0.06, FACS analysis for Sca-1+/Flk-1+ cells), suggesting that IGF-1 promotes vascular repair. In summary, IGF-1 markedly suppresses systemic and vascular oxidant stress and reduces atherosclerosis progression in ApoE-deficient mice. The finding that IGF-1 has antioxidant and anti-atherogenic properties establish a new paradigm for biological effects of IGF-1 and has major implications for treating atherosclerosis and its complications.