FoxO4 inhibits atherosclerosis through its function in bone marrow derived cells

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Atherosclerosis (Impact Factor: 3.99). 12/2011; 219(2):492-8. DOI: 10.1016/j.atherosclerosis.2011.09.038
Source: PubMed

ABSTRACT FoxO proteins are transcription factors involved in varieties of cellular processes, including immune cell homeostasis, cytokine production, anti-oxidative stress, and cell proliferation and differentiation. Although these processes are implicated in the development of atherosclerosis, very little is known about the role of FoxO proteins in the context of atherosclerosis. Our objectives were to determine whether and how inactivation of Foxo4, a member of the FoxO family, in vivo promotes atherosclerosis.
Apolipoprotein E-deficient (apoE(-/-)) mice were crossbred with animals lacking Foxo4 (Foxo4(-/-)). After 10 weeks on a high fat diet (HFD), Foxo4(-/-)apoE(-/-) mice showed elevated atherosclerosis and increased amount of macrophages and T cells in the plaque compared to apoE(-/-) mice. Bone marrow transplantations of chimeric C57B/6 mice reconstituted with either wild-type or Foxo4(-/-) bone marrows indicate that Foxo4-deficiency in bone marrow derived cells sufficiently promoted atherosclerosis. Foxo4-null macrophages produced elevated inflammatory cytokine IL-6 and levels of reactive oxygen species (ROS) in response to lipopolysaccharides in vitro. Serum levels of IL-6 were upregulated in HFD-fed Foxo4(-/-)apoE(-/-) mice compared to those of apoE(-/-) mice.
FoxO4 inhibits atherosclerosis through bone marrow derived cells, possibly by inhibition of ROS and inflammatory cytokines that promote monocyte recruitment and/or retention.

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    • "FOXO1 knockout mice die in utero due to defective vasculature (Hosaka et al., 2004), FOXO3 knockout mice suffer from organ inflammation resulting from defective development of regulatory T-cells (Harada et al., 2010; Kerdiles et al., 2010). In contrast FOXO4 and FOXO6 knockout mice present with mild phenotypes (Zhu et al., 2011; Salih et al., 2012). Conditional triple-knock-out in the adult mouse causes a relatively mild neoplastic phenotype, i.e., these mice develop hemangiomas and thymic lymphomas, which suggests that FOXO1, FOXO3, and FOXO4 are involved in the maintenance of the hematopoietic stem cell population and the regulation of endothelial cell homeostasis (Paik et al., 2007; Tothova et al., 2007). "
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    ABSTRACT: Forkhead box O (FOXO) transcription factors are regulators of cell-type specific apoptosis and cell cycle arrest but also control longevity and reactive oxygen species (ROS). ROS-control by FOXO is mediated by transcriptional activation of detoxifying enzymes such as Superoxide dismutase 2 (SOD2), Catalase or Sestrins or by the repression of mitochondrial respiratory chain proteins resulting in reduced mitochondrial activity. FOXO3 also regulates the adaptation to hypoxia by reducing mitochondrial mass and oxygen consumption during HIF-1α activation. In neuronal tumor cells, FOXO3 triggers ROS-accumulation as a consequence of transient mitochondrial outer membrane permeabilization, which is essential for FOXO3-induced apoptosis in these cells. Cellular ROS levels are affected by the FOXO-targets Bim, BclxL, and Survivin. All three proteins localize to mitochondria and affect mitochondrial membrane potential, respiration and cellular ROS levels. Bim-activation by FOXO3 causes mitochondrial depolarization resulting in a transitory decrease of respiration and ROS production. Survivin, on the other hand, actively changes mitochondrial architecture, respiration-efficacy and energy metabolism. This ability distinguishes Survivin from other anti-apoptotic proteins such as BclxL, which inhibits ROS by inactivating Bim but does not alter mitochondrial function. Importantly, FOXO3 simultaneously also activates ROS-detoxification via induction of SESN3. In this paper we discuss the hypothesis that the delicate balance between ROS-accumulation by Bim-triggered mitochondrial damage, mitochondrial architecture and ROS-detoxifying proteins determines cell fate. We provide evidence for a FOXO self-reactivating loop and for novel functions of FOXO3 in controlling mitochondrial respiration of neuronal cells, which further supports the current view that FOXO transcription factors are information-integrating sentinels of cellular stress and critical modulators of cell homeostasis.
    Frontiers in Physiology 06/2013; 4:147. DOI:10.3389/fphys.2013.00147 · 3.53 Impact Factor
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    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.
    Circulation Research 02/2013; 112(7). DOI:10.1161/CIRCRESAHA.112.300749 · 11.02 Impact Factor
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    Circulation Research 03/2013; 112(7):978-82. DOI:10.1161/CIRCRESAHA.113.301159 · 11.02 Impact Factor


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