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IGF‐1 Receptor on Leukocytes Potentiates Western Diet‐induced Inflammatory Response and Progression of Atherosclerosis in ApoE‐Deficient Mice
Author(s) -
Wang Meifang,
Higashi Yusuke,
Wang Derek,
Yu Hong,
Delafontaine Patrice,
Korthuis Ronald
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.679.8
Subject(s) - apolipoprotein e , endocrinology , medicine , knockout mouse , monocyte , inflammation , receptor , biology , apolipoprotein b , immunology , cholesterol , disease
Atherosclerosis is the principal underlying cause of most cardiovascular disease‐related deaths, the leading cause of mortality in the US. Insulin‐like growth factor‐1 (IGF‐1), the primary mediator of the effect of growth hormone on developmental growth, is expressed in vascular cells and monocytes/macrophages. However, IGF‐1's role in atherosclerosis is unknown. Our previous studies showed that lowered circulating IGF‐1 increases atherosclerosis progression in atherosclerosis‐prone apolipoprotein E‐deficient mice (ApoE −/− ) while increased circulating IGF‐1 downregulates expression of vascular pro‐inflammatory cytokines, reduces systemic and vascular oxidant stress, and decreases atherosclerosis progression. We also demonstrated that that the aforementioned inflammatory phenotype is potentiated in mice with double knockout of ApoE and IGF1 receptor (IGF1R), where IGF1R expression was selectively deleted in monocyte/macrophages (ApoE −/− LC), and that consumption of a Western diet enhanced monocyte‐endothelial interactions in these double knockout mice compared to wild type IGF‐1R/ApoE −/− ‐flox mice (ApoE −/− ‐FIR). Here, we examined similar endpoints in an ApoE/IGFR1 −/− model in which IGF1R‐expression was selectively deleted in endothelial cells (ApoE −/− VF), and again examined the possible interaction of the effect of these knockouts with consumption of a Western diet, comparing ApoE −/− VF with IGF‐1R ApoE −/− ‐flox mice (ApoE −/− ‐FIR). We compared baseline Leukocyte Rolling (LR) and Leukocyte Adhesion (LA) in both these mice fed either normal mouse chow (NC) or Western diet (WD). There was significant increase in the pro‐inflammatory phenotype in both NC fed mice (ApoE −/− VF NC and ApoE −/− ‐FIR NC) compared to C57BL6 wild type mice. Ingestion of a Western Diet markedly enhanced LR and LA on both ApoE −/− VF animals (ApoE −/− VF WD) and ApoE −/− ‐FIR animals (ApoE −/− ‐FIR WD), however. This finding indicates that the pro‐inflammatory phenotype enhanced by WD in ApoE − / − VF and FIR mice is not further enhanced by specific IGF1R deficiency in endothelial cells. We conclude that IGF‐1 receptor on leukocytes, but not endothelial cells, potentiates the inflammatory phenotype induced by Western Diet in ApoE‐deficient mice. Support or Funding Information Supported by NIH: R01‐HL59976, RO1 HL070241 and HL 080682, R01‐AA22108.