Abstract 17103: Insulin-like Growth Factor I (IGF-1) Suppresses Chemokines and Reduces Recruitment of Monocytes into Atherosclerotic Plaque: Potential Mechanism Mediating IGF-1-induced Atheroprotection
We have shown that IGF-1 decreases plaque macrophages (MF) and reduces atherosclerotic burden in high fat fed Apoe-null mice. We hypothesized that IGF-1 suppresses recruitment of circulating monocytes (MN) into atherosclerotic plaques. To test whether IGF-1 regulates MN recruitment into plaques, Apoe-null mice were fed with a high fat diet for 8 wks, IGF-1 was administrated for the last 7d (25 ug/d, i.p) and circulating MN were specifically labeled by i.v. injection of red latex beads. IGF-1 reduced levels of Mac3-positive/red-labeled cells in plaques (IGF-1: 1.05±0.3 cells/plaque vs. control: 1.8±0.2, P<0.05) without affecting labeled splenic MN. Similarly, IGF-1 long-term administration (mini-pumps, 1.5 mg/kg/d, 4 wks) decreased labeled MF in plaques (IGF-1: 1.3±0.3 cells/plaque vs. control: 2.6±0.4, P<0.05), indicating that IGF-1 suppressed MN infiltration into plaques. We then generated MN/MF-specific (scavenger receptor A-promoter driven) IGF-1 overexpressor Apoe-null mice (SRA mice). Peritoneal MF from SRA mice had increased IGF-1 secretion (52±9% vs. control). High fat diet fed SRA mice had reduced plaque MF levels (Mac3 staining, 27.5±7% decrease), and decreased atherosclerotic burden in both aortic valve (23±6% decrease) and aorta (En face analysis, 28.4±1.2% decrease). SRA females had reduced serum levels of monocyte chemoattractant protein-1 (MCP-1) (45±15% decrease). MCP-1 is known to mediate MN recruiting into plaques. Further, IGF-1 (50 ng/ml, 24h) decreased MCP-1 (43±6% decrease), and also reduced chemokine receptors CCR1 (40±4% decrease) and CCR2 (38±5% decrease) in cultured human THP-1 MN. IGF-1 also suppressed adhesion of calcein-labeled MN to endothelial cells (EC, 22±4% decrease). In summary, systemic IGF-I administration suppressed MN recruitment into plaques and MN/MF-specific IGF-1 decreased MCP-1, reduced plaque MF and decreased atherosclerotic burden in Apoe-null mice. IGF-1 reduced chemokine expression in cultured MF and IGF-1 decreased MN adhesion to EC. These data suggest that IGF-1-induced chemokines downregulation suppresses MN recruitment into plaques and reduces atherosclerotic burden. IGF-1 has a therapeutic potential in atherosclerosis.
Author Disclosures: P. Snarski: None. S. Sukhanov: None. S. Shai: None. Y. Higashi: None. P. Delafontaine: None.
- © 2016 by American Heart Association, Inc.