We have shown that insulin‐like growth factor I (IGF‐1) reduced atherosclerosis in Apoe‐null mice. We also reported that deficiency for macrophage (MF)‐specific IGF‐1 receptor (IGF1R) upregulated matrix metalloproteinases (MMPs), decreased MMP inhibitor RECK (reversion inducing cysteine rich protein with kazal motifs) and promoted atherogenesis. To study whether increase in MF IGF‐1 will suppress MMPs and decrease atherosclerosis, we generated Apoe‐null mice with IGF‐1 overexpression driven by MF‐specific promoter (scavenger receptor A) called SRA mice and we also performed experiments with cultured THP‐1 macrophages. THP‐1 MFs were incubated with IGF‐1 (0, 20, 100ng/mL) for 48 hrs. IGF‐1 (20 ng/ml) decreased expression of MMP8 (34+/−13% decrease, P<0.05) and MMP14 protein (35+/−17% decrease, P<0.05) as quantified by ELISA. To demonstrate that IGF‐1 effect on MMPs was mediated via IGF1R‐dependent mechanism, we used Picropodophyllin (PPP), a specific IGF1R inhibitor. MF pre‐treatment with PPP (1 ug/ml, 2hrs) completely abolished IGF‐1‐induced MMP8 downregulation in MF. We generated two mouse lines overexpressing IGF‐1 in MF: SRA12 and SRA17. IGF‐1 level was increased in peritoneal MF isolated from SRA12 (21±4% increase) and from SRA17 mice (52±9% increase) compared to control Apoe‐null mice (both are P<0.05). SRA12 and SRA17 mice were fed with a high fat diet for 12 weeks. MF‐specific IGF‐1 overexpression significantly decreased atherosclerotic burden (SRA12, 23±3% decrease, n=20, and SRA17, 28±6% decrease, n=16, vs. control, n=29, en face analysis) and increased plaque collagen levels (11.1±6%, SRA12 and 66.5±11%, n=11, SRA17, Trichrome staining). Atherosclerotic plaques in both SRA12 and SRA17 mice had reduced necrotic cores suggesting elevated plaque stability. Of note, the increased levels of plaque collagen in SRA17 mice correlated with a significant decrease of MMP1, MMP2, MMP8, MMP12, MMP13, and MMP14 protein levels in peritoneal MF (immunoblotting, 30–72% decrease vs. control). Protein level of RECK was increased in both SRA12 and SRA17 peritoneal MF. In summary, we show that IGF‐1 reduced MMPs in vitro and MF IGF‐1 decreased MMPs, upregulated collagen and suppressed atherosclerotic burden in vivo. Thus, we identified the novel MMP‐ (and collagen) dependent mechanism potentially mediating MF IGF‐1 atheroprotective effect.Support or Funding InformationNIH/NHLNI 2R01HL070241‐13A1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.