Abstract 13304: Insulin-like Growth Factor I (IGF-1) Reduces Lipid Oxidation and Foam Cell Formation via Downregulation of 12/15-lipoxygenase
We have previously shown that IGF-1 infusion in Apoe-/- mice decreased atherosclerotic plaque size, macrophages (MF) and lipids suggesting that IGF-1 suppressed MF-derived foam cell formation. 12/15-lipoxygenase (LOX) promotes oxidation of low density lipoprotein (LDL) and MF uptake of oxidized LDL (OxLDL) to form foam cells.
We found that IGF-1 infusion (1.5 mg/kg/d) in Apoe-/- mice fed a Western diet decreased plaque LOX expression (immunostaining, 67±6% decrease) and aortic LOX mRNA (36±4% decrease). IGF-1 reduced serum OxLDL (19.7% decrease) and malondialdehyde (a marker of lipid oxidation, 22% decrease), suggesting that IGF-1 suppressed lipid oxidation. To determine the effects of IGF-1 on lipid oxidation and the role of LOX we exposed human THP-1 MF to 0-50 ng/ml IGF-1 for 0-24 h. IGF-1 dose- and time-dependently reduced LOX protein and mRNA levels (49±5% and 48±6% decrease at 24 h, Western blotting and RT-PCR, respectively) and decreased expression of STAT-6 transcription factor (38±4% decrease). STAT6-specific siRNA reduced both STAT6 and LOX protein levels indicating STAT6 involvement in LOX transcriptional regulation. IGF-1-induced LOX decrease was prevented by PI3 kinase inhibition (LY2940032, 50 uM). Incubation of IGF-1-treated THP-1 MF with LDL (150 ug/ml, 48h) showed that IGF-1 markedly suppressed the ability of MF to oxidize lipids (TBARS assay, 65±4% decrease) and to form foam cells (Oil Red staining, 64±4% decrease). Peritoneal MF from LOX-/- mice had a basal reduction in cell-mediated LDL oxidation and foam cell formation vs. wild type (WT) MF. IGF-1 reduced LDL oxidation and formation of foam cells by WT MF but these effects were blocked in LOX-/- MF suggesting that the ability of IGF-1 to reduce LDL oxidation and foam cell formation was dependent on its ability to downregulate LOX.
Thus, IGF-1 reduced LOX expression in atherosclerotic plaques and suppressed lipid oxidation in Apoe-/- mice. IGF-1 decreased LOX expression in cultured MF via a PI3 kinase- and -STAT6 dependent transcriptional mechanism, resulting in marked reduction in MF-mediated LDL oxidation and foam cell formation. These data strongly suggest that IGF-1-induced MF LOX downregulation plays a major role in the ability of IGF-1 to exert anti-atherosclerotic effects.
Author Disclosures: S. Sukhanov: Research Grant; Significant; NHLBIR21 grant, PI. P. Snarski: None. P. Lobelle-Rich: None. C. Vaughn: None. C. Kim: None. P. Delafontaine: Research Grant; Significant; NIH/NHLBI R01.
- © 2014 by American Heart Association, Inc.