Abstract 13415: Monocyte/Macrophage-Specific Insulin-Like Growth Factor-1 Receptor Deficiency Promotes Lipid Accumulation and Inflammatory Responses in Macrophages, Leading to Increased Atherosclerosis
Macrophage (Mf) uptake of modified lipids, pro-inflammatory signaling and conversion to foam cells is a hallmark of atheroma formation. Insulin-like growth factor-1 (IGF-1) is a pleiotropic growth factor and its receptor (IGF1R) is expressed in various cell types including Mf, yet the role of Mf IGF1R signaling in atherogenesis is unknown. We created Mf-specific IGF1R-deficient mice on Apoe-/- background (Mf-IGF1R-KO) and found these mice had increased plaque burden (aortic root plaque size, 57.0 ± 14.9 % increase) and enhanced inflammatory phenotype (anti-Mac3 staining, Mf-IGF1R-KO, 31.3 ± 2.8 % vs. IGF1R flox, 22.5 ± 4.2 %). To determine mechanisms we exposed peritoneal Mf from Mf-IGF1R-KO mice (IGF1R-KO cells) and IGF1R-flox mice (IGF1R-WT cells) to acetylated LDL (acLDL) and oxidized LDL (oxLDL) and assessed proinflammatory cytokine and chemokine expression levels, lipid uptake, and cholesterol efflux. IGF1R-KO cells expressed higher levels of IL1α, IL6, and TNFα compared to IGF1R-WT cells (IL1α; 338±19 pg/mg protein vs. 32±1 pg/mg protein, P<0.01, IL6; 1167±37 pg/mg protein vs. 30±2, P<0.01, TNFα; 240±72 pg/mg protein vs. Not Detectable), whereas oxLDL did not further enhance cytokine expression. NFkB activity was significantly higher in IGF1R-KO cells than IGF1R-WT cells as determined by a solid-phase DNA binding assay. AcLDL or oxLDL uptake was not altered by IGF1R deficiency; however cholesterol efflux to apolipoprotein A1 was significantly impaired (decreased by 57.9±9.4 %, P<0.01). OxLDL upregulation of ATP-binding cassette transporter A1 was suppressed by 40.8±5.9 % (P<0.05) in IGF1R-KO cells indicating that IGF1R-deficiency impaired lipid efflux thereby promoting macrophage foam cell formation. Moreover, there was a concomitant decrease in oxLDL-upregulation of diacylglycerol acyltransferase 1, consistent with dysregulation of lipid homeostasis. Thus Mf IGF-1R deficiency is markedly pro-inflammatory and disrupts Mf lipid trafficking by reducing cholesterol efflux, resulting in increased atherosclerotic plaque formation. These data suggest that IGF-1 regulation of Mf inflammatory responses and lipid metabolism may provide a novel therapeutic approach for the treatment of atherosclerotic vascular disease.
Author Disclosures: Y. Higashi: None. S. Shai: None. S. Sukhanov: Research Grant; Significant; NHLBIR21 grant, PI. P. Delafontaine: None.
- © 2014 by American Heart Association, Inc.