We also found a 27% increase in cholesterol efflux in IGF1 (100 ng/mL) treated THP-1 cells with Apolipoprotein AI as a cholesterol acceptor. We loaded peritoneal macrophages with oxLDL to measure changes in cholesterol efflux and found that MF-IGF1 mice have a 42% increase in efflux. We found that peritoneal macrophages isolated from MF-IGF1 mice have a 2 fold increase in ABCA1 protein levels.
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.ĪTP-binding cassette transporter A1 (ABCA1) is the key cholesterol transporter mediating macrophage cholesterol efflux and CXCL12 reduces its expression. CXCL12 protein levels were reduced in plaque and peritoneal macrophages in MF-IGF1 mice. Monocyte recruitment was reduced by 70% in MF-IGF1 mice and was associated with a 27% reduction in circulating levels of CXC Chemokine Ligand 12 (CXCL12). Macrophage IGF1 overexpression downregulated plaque burden by 30%, reduced plaque macrophages by 47%, and promoted features of a stable plaque phenotype. We also assessed cholesterol efflux and foam cell formation in vivo and in vitro. We accelerated atherosclerotic development by feeding animal a high fat diet for three months. We hypothesized that increasing IGF1 levels strictly in macrophages will prevent atherosclerosis.Īfter 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. Results of our previous in vitro experiments suggest that macrophages play a predominant role in mediating IGF1 effects in atherosclerotic plaque, but exact mechanisms remain unclear.
IGF1 administration in ApoE deficient (Apoe -/-) mice fed a high fat diet reduced atherosclerosis and reduced plaque macrophages. Insulin Like Growth Factor I (IGF1) has been shown to reduce cardiovascular events. 1Tulane University School of Medicine, New Orleans, LAĢUniversity of Missouri System, Columbia, MOĪtherosclerosis is the leading cause of Cardiovascular Disease, which is still the global leader of mortality.
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