Insulin‐like growth factor I downregulates proatherogenic 12/15‐lipoxygenase in vivo and in vitro

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We have shown that 12/15‐lipoxygenase (LOX) mediates important proatherogenic oxidized low density lipoprotein (OxLDL)‐induced effects in smooth muscle cells (SMC), namely, apoptosis and downregulation of the insulin‐like growth factor (IGF‐1) receptor, and that infusion of IGF‐1 into Apolipoprotein E‐null (ApoE‐/‐) mice suppresses macrophage (MF) plaque infiltration and atherosclerosis. To determine molecular mechanisms mediating IGF‐1's anti‐atherogenic effects ApoE‐\‐ mice were injected with IGF‐1 (0.7 mg/kg/day, 7d). IGF‐1 decreased LOX aortic gene expression by 64±6% (RT‐PCR). IGF‐1 dose‐dependently decreased LOX gene expression in THP‐1 derived MF, while no significant effect was seen in SMC. To examine IGF‐1's effects on LOX activity, SMC or MF were pre‐treated with IGF‐1 (10 or 50 ng/ml, 24h), and then exposed to OxLDL or control. 14,15‐leukotriene (a product of LOX‐specific enzymatic reaction) levels were measured in conditioned media by ELISA. OxLDL induced a five‐fold increase in LOX activity levels in MF, and a smaller increase in LOX activity in SMC. IGF‐1 partially blocked OxLDL‐induced LOX upregulation by 27±4%. In summary, IGF‐1 suppresses vascular LOX expression in ApoE‐\‐ mice and induces LOX downregulation in MΦ and SMC. Our data suggests that the ability of IGF‐1 to downregulate LOX plays an important role in its anti‐atherogenic effect.Study supported by NIH HL 70241