Expanded granulocyte/monocyte compartment in myeloid-specific triple FoxO knockout increases oxidative stress and accelerates atherosclerosis in mice

Kyoichiro Tsuchiya, Marit Westerterp, Andrew J Murphy, Vidya Subramanian, Anthony W Ferrante, Alan R Tall, Domenico Accili

Research output: Contribution to journalArticleAcademicpeer-review

50 Citations (Scopus)

Abstract

RATIONALE: Increased neutrophil and monocyte counts are often associated with an increased risk of atherosclerosis, but their relationship to insulin sensitivity is unknown.

OBJECTIVE: To investigate the contribution of forkhead transcription factors (FoxO) in myeloid cells to neutrophil and monocyte counts, atherosclerosis, and systemic insulin sensitivity.

METHODS AND RESULTS: Genetic ablation of the 3 genes encoding FoxO isoforms 1, 3a, and 4, in myeloid cells resulted in an expansion of the granulocyte/monocyte progenitor compartment and was associated with increased atherosclerotic lesion formation in low-density lipoprotein receptor knockout mice. In vivo and ex vivo studies indicate that FoxO ablation in myeloid cells increased generation of reactive oxygen species. Accordingly, treatment with the antioxidant N-acetyl-l-cysteine reversed the phenotype, normalizing atherosclerosis.

CONCLUSIONS: Our data indicate that myeloid cell proliferation and oxidative stress can be modulated via the FoxO branch of insulin receptor signaling, highlighting a heretofore-unknown link between insulin sensitivity and leukocytosis that can affect the predisposition to atherosclerosis.

Original languageEnglish
Pages (from-to)992-1003
Number of pages12
JournalCirculation research
Volume112
Issue number7
DOIs
Publication statusPublished - 2013

Keywords

  • Acetylcysteine/pharmacology
  • Animals
  • Antioxidants/pharmacology
  • Apoptosis/physiology
  • Atherosclerosis/metabolism
  • Cysteine/metabolism
  • Female
  • Forkhead Box Protein O1
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors/genetics
  • Free Radical Scavengers/pharmacology
  • Hematopoietic Stem Cells/metabolism
  • Insulin/metabolism
  • Macrophages/metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Monocytes/metabolism
  • Neutrophils/metabolism
  • Nitrogen/metabolism
  • Oxidative Stress/drug effects
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/drug effects
  • Tyrosine/metabolism

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