Abstract 13299: Insulin-like Growth Factor I (IGF-1) Reduces Chemokines and Recruitment of Monocytes Into Atherosclerotic Plaque: Potential Mechanism Mediating IGF-1-induced Atheroprotection
We have shown that IGF-1 infusion decreased atherosclerotic plaque burden and macrophage content in Apoe-/- mice. We hypothesized that IGF-1 suppressed recruitment of circulating monocytes (MN) into plaque.
Apoe-/- mice on a Western diet for 8 wks received IGF-1 (25 ug i.p. daily, 1 wk) and red latex beads (2.5% wt/vol in PBS, i.v., specifically taken up by MN). IGF-1 reduced Mac3 (macrophage marker)-positive/red-labeled cells in plaque (1.05±0.3, IGF-1 vs.1.8±0.2 cells/plaque, control) without changes in labeled splenic MN. Similarly, chronic IGF-1 delivery (1.5 mg/kg/d, 4 wks, mini-pumps) decreased labeled plaque MN (1.3±0.3, IGF-1 vs. 2.6±0.4 cells/plaque, control). Conversely, mice with MN/macrophage-specific IGF-1 receptor deficiency (LCFIR) had increased labeled plaque MN (5.73±0.8, LCFIR vs. 2.33±0.4 cells/plaque, control). MN chemotaxis is mediated by multiple chemokines/chemokine receptors. 6T/E mice are congenic mice on Apoe-/- background that have a 20% decline in circulating IGF-I and increased atherosclerosis. Compared with wild-type (WT) 6T/E mice had increased mRNA levels of chemokines in atherosclerotic aortas (RT array, MCP-1, 185%; CCR1, 118%; CCR2, 99% increase vs. WT) and increased levels of circulating chemokines (Milliplex ELISA, MCP-1, 19.7 vs. 7.6 pg/ml; CXCL1, 74.4 vs. 24.9 pg/ml; E-selectin, 70.1 vs. 48.9 pg/ml, 6T/E vs. WT). To determine mechanisms we quantified IGF-1 effects on chemokines and on MN adhesion using human THP-1 MN. IGF-1 (50 ng/ml, 24h) significantly decreased MCP-1 (43±6% decrease), CCR1 (40±4% decrease) and CCR2 (38±5% decrease) mRNA in THP-1 cells and suppressed adhesion of calcein-labeled MN to endothelial cells (22±4% decrease, P<0.05).
Thus, IGF-I reduced MN recruitment into plaque in Apoe-/- mice and loss of MN IGF-1R signaling increased monocyte recruitment. A decrease in IGF-1 levels markedly increased vascular and circulating chemokine expression in Apoe-/- mice and conversely IGF-1 suppressed chemokine expression in THP-1 cells, resulting in reduced adhesion to endothelial cells. Taken together these data suggest that IGF-1 downregulation of chemokines reduces MN recruitment into atherosclerotic plaque and plays a critical role in mediating anti-atherosclerotic effects of IGF-1.
Author Disclosures: S. Sukhanov: Research Grant; Significant; NHLBIR21 grant, PI. P. Snarski: None. P. Delafontaine: Research Grant; Significant; NIH/NHLBI R01.
- © 2014 by American Heart Association, Inc.