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Circ Res. 2013 Mar 29;112(7):992-1003. doi: 10.1161/CIRCRESAHA.112.300749. Epub 2013 Feb 18.

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

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1
Naomi Berrie Diabetes Center, 1150 St Nicholas Ave, Russ Berrie Pavilion Room 238, NY 10032, USA.

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.

PMID:
23420833
PMCID:
PMC3736810
DOI:
10.1161/CIRCRESAHA.112.300749
[Indexed for MEDLINE]
Free PMC Article

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