title: Expanded granulocyte/monocyte compartment in myeloid-specific triple FoxO knockout increases oxidative stress and accelerates atherosclerosis in mice.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Naomi Berrie Diabetes Center, 1150 St Nicholas Ave, Russ Berrie Pavilion Room 238, NY 10032, USA.
authors: Kyoichiro
authors: K
authors: Tsuchiya
authors: Marit
authors: M
authors: Westerterp
authors: Andrew J
authors: AJ
authors: Murphy
authors: Vidya
authors: V
authors: Subramanian
authors: Anthony W
authors: AW
authors: Ferrante
authors: Alan R
authors: AR
authors: Tall
authors: Domenico
authors: D
authors: Accili
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018797:Cell Cycle Proteins; D003545:Cysteine / Q000378:metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018797:Cell Cycle Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; D016166:Free Radical Scavengers; D007328:Insulin; D014443:Tyrosine; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D003545:Cysteine; D009584:Nitrogen; D000111:Acetylcysteine