Adipose-Derived Exosomes Exert Proatherogenic Effects by Regulating Macrophage Foam Cell Formation and Polarization

J Am Heart Assoc. 2018 Mar 3;7(5):e007442. doi: 10.1161/JAHA.117.007442.

Abstract

Background: Obesity is causally associated with atherosclerosis, and adipose tissue (AT)-derived exosomes may be implicated in the metabolic complications of obesity. However, the precise role of AT-exosomes in atherogenesis remains unclear. We herein aimed to assess the effect of AT-exosomes on macrophage foam cell formation and polarization and subsequent atherosclerosis development.

Methods and results: Four types of exosomes isolated from the supernatants of ex vivo subcutaneous AT and visceral AT (VAT) explants that were derived from wild-type mice and high-fat diet (HFD)-induced obese mice were effectively taken up by RAW264.7 macrophages. Both treatment with wild-type VAT exosomes and HFD-VAT exosomes, but not subcutaneous AT exosomes, markedly facilitated macrophage foam cell generation through the downregulation of ATP-binding cassette transporter (ABCA1 and ABCG1)-mediated cholesterol efflux. Decreased expression of liver X receptor-α was also observed. Among the 4 types of exosomes, only HFD-VAT exosomes significantly induced M1 phenotype transition and proinflammatory cytokine (tumor necrosis factor α and interleukin 6) secretion in RAW264.7 macrophages, which was accompanied by increased phosphorylation of NF-κB-p65 but not the cellular expression of NF-κB-p65 or IκB-α. Furthermore, systematic intravenous injection of HFD-VAT exosomes profoundly exacerbated atherosclerosis in hyperlipidemic apolipoprotein E-deficient mice, as indicated by the M1 marker (CD16/32 and inducible nitric oxide synthase)-positive areas and the Oil Red O/Sudan IV-stained area, without affecting the plasma lipid profile and body weight.

Conclusions: This study demonstrated a proatherosclerotic role for HFD-VAT exosomes, which is exerted by regulating macrophage foam cell formation and polarization, indicating a novel link between AT and atherosclerosis in the context of obesity.

Keywords: adipose tissue; atherosclerosis; exosome; macrophage; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism
  • Animals
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology*
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Disease Models, Animal
  • Disease Progression
  • Exosomes / metabolism
  • Exosomes / pathology
  • Exosomes / transplantation*
  • Foam Cells / metabolism
  • Foam Cells / pathology*
  • Intra-Abdominal Fat / metabolism
  • Intra-Abdominal Fat / pathology
  • Intra-Abdominal Fat / transplantation*
  • Liver X Receptors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout, ApoE
  • Obesity / metabolism
  • Obesity / pathology*
  • Phenotype
  • Phosphorylation
  • Plaque, Atherosclerotic*
  • RAW 264.7 Cells
  • Subcutaneous Fat / metabolism
  • Subcutaneous Fat / pathology
  • Subcutaneous Fat / transplantation*
  • Time Factors
  • Transcription Factor RelA / metabolism

Substances

  • ABCA1 protein, mouse
  • ABCG1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • Liver X Receptors
  • Nr1h3 protein, mouse
  • Rela protein, mouse
  • Transcription Factor RelA
  • Cholesterol