Abstract 13092: Macrophage Specific IGF1 Overexpression on ApoE Deficient Mice Decreases Atherosclerosis, Reduces CXCL12 Chemokine Expression, and Increases Cholesterol Efflux

Increased bioavailability of Insulin Like Growth Factor I (IGF1) has been shown to reduce cardiovascular events. Systemic IGF1 administration in ApoE deficient (Apoe -/- ) mice fed a high fat diet reduced atherosclerosis and reduced plaque macrophages. Results of our previous in vitro experiments suggest that macrophages play a predominant role in mediating IGF1 effects in atherosclerotic plaque. We hypothesized that increasing IGF1 levels strictly in macrophages will prevent atherosclerosis. After breeding a novel macrophage-specific IGF1 overexpressing transgenic mouse to an Apoe -/- background (MF-IGF1 mice), we assessed atherosclerotic plaque burden, stability, and monocyte recruitment. Macrophage IGF1 overexpression downregulated plaque burden by 30% (P<0.01), reduced plaque macrophages by 47% (P<0.001) and promoted a stable plaque phenotype. Monocyte recruitment was reduced by 70% (P<0.05) in MF-IGF1 mice and was associated with a decrease in circulating levels of CXC Chemokine Ligand 12 (CXCL12) (27% reduction, P<0.05). CXCL12 protein levels were reduced in plaque and peritoneal macrophages in MF-IGF1 mice. IGF1 completely blocked oxidized low-density lipoprotein (oxLDL)-dependent increase of CXCL12 mRNA transcription (98% reduction, P<0.01) and IGF1 treatment reduced CXCL12 protein (56% decrease, P<0.001) in vitro. ATP-binding cassette transporter A1 (ABCA1) is the key cholesterol transporter mediating macrophage cholesterol efflux and CXCL12 reduces its expression. We found that peritoneal macrophages isolated from MF-IGF1 mice have a 2 fold increase in ABCA1 protein levels. We loaded peritoneal macrophages with oxLDL to measure changes in cholesterol efflux and found that MF-IGF1 mice have a 42% increase in efflux (P<0.01). We also found a 27% increase in cholesterol efflux in IGF1 (100 ng/mL) treated THP-1 cells (P<0.01) with Apolipoprotein AI as a cholesterol acceptor. Overall, our results indicate that macrophage IGF1 reduces atherosclerosis and decreases CXCL12, a chemokine newly implicated in atheroprogression. IGF1 potentially exerts its atheroprotective effect via this reduction in CXCL12 by reducing monocyte recruitment and by increasing ABCA1, thereby increasing cholesterol efflux capacity.