Macrophage Insulin‐Like Growth Factor I (IGF1) Upregulates Atherosclerotic Plaque Collagen and Suppresses Atherosclerosis by Reducing Matrix Metalloproteinases.

Abstract

We have shown that IGF1 decreased atherosclerotic burden in high fat diet fed Apoe‐null mice and we have also demonstrated that decline in macrophage (MF) IGF1 signaling promoted murine atherogenesis. To test whether an increase in MF IGF1 would prevent atherogenesis, we generated Apoe‐null mice with MF‐specific scavenger receptor A promoter‐driven IGF1 overexpression: SRA12 and SRA17 mice. Peritoneal MF isolated from SRA12 and SRA17 mice had increased IGF‐1 secretion (21±4% and 52±9% increase vs. Apoe‐null mice, control, respectively). High fat fed SRA12 and SRA17 mice have significantly decreased atherosclerotic burden in aortic valve (SRA12, 23±3% decrease, n=20, and SRA17, 28±6% decrease, n=16, vs. control, n=29) and in whole aorta preparations (En face analysis, % lesion area per aorta area: SRA‐12, 7.3±0.5%, SRA‐17, 7.1±0.5%, vs. control, 10.1±0.7%) showing that MF IGF1 suppressed atherogenesis. Plaques in SRA12 and SRA17 mice had decreased MF (Mac‐3 IHC, 27.8±6% and 29.5±5% decrease, respectively, both p<0.05), and reduced necrotic core (29±3% and 27±3% decrease, respectively, both p<0.05), and increased collagen (Trichrome, 11.1±6%, p=NS and 66.5±11% increase, p<0.005, respectively), suggesting elevated plaque stability. To identify mechanism mediating collagen increase in SRA17 mice we quantified protein expression of matrix metalloproteinases (MMPs) in peritoneal MF. MMP1, MMP2, MMP8, MMP12, MMP13 and MMP14 levels were significantly reduced (30–72% decrease) only in SRA17 MF and no changes were found in MMPs expression in SRA12 MF. Protein level of MMP inhibitor RECK (reversion inducing cysteine rich protein with kazal motifs) was increased in both SRA17 and SRA12 peritoneal MF (2.6‐ and 1.9‐fold increase, respectively). Blood monocytes isolated from SRA17 and SRA12 mice had reduced MMP14 mRNA levels (RT‐PCR, 40.1±40.4% decrease, P<0.05 and 26±61.7% decrease, P=0.1263, respectively). To assess IGF1 effect on MMPs in vitro we used cultured human THP‐1 MF. IGF1 dose‐ and time‐dependently reduced MMP8 expression in THP‐1 cells (MMP8 ELISA: 20ng/ml IGF1, 26.3±16.7% decrease, 100 ng/ml IGF1, 42.3±3.07% decrease, both p<0.05 ). In summary, we found that either relatively small or large increase in macrophage IGF1 (in SRA12 or SRA17 mice, respectively) downregulated plaque macrophages, decreased necrotic core and reduced atherosclerotic burden. Interestingly, only a large increase in IGF1 (in SRA17 mice) suppressed MMPs and increased plaque collagen suggesting that these effects of IGF1 were dose‐dependent. Consistent with these in vivo results, IGF‐1 suppressed MMP8 in THP‐1 MF. Thus, we identified novel MMP‐and dose‐dependent mechanism contributing to IGF1‐induced upregulation of plaque collagen and suppression of atherosclerosis.Support or Funding InformationNIH/NHLBI 2R01HL070241‐13A1This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.