The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis

Loebel, Madlen; Holzhauser, Luise; Hartwig, Jelka; Shukla, Praphulla Chandra; Savvatis, Konstantinos; Jenke, Alexander; Gast, Martina; Escher, Felicitas; Becker, S; Bauer, Sandra; Stroux, Andrea; Beling, Antje; Kespohl, Meike; Pinkert, Sandra; Fechner, Henry; Kuehl, Uwe; Laßner, Dirk; Poller, Wolfgang; Schultheiss, Heinz‐Peter; Zeller, Tanja; Blankenberg, Stefan; Papageorgiou, Anna-Pia; Heymans, Stéphane; Landmesser, Ulf; Scheibenbogen, Carmen; Skurk, Carsten

doi:10.1093/eurheartj/ehx624

Cited by 24 publications

(26 citation statements)

References 204 publications

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“…In the study by Lee et al monocytes from healthy subjects carrying the SNP rs12212067 had lower TNF-a response upon LPS stimulation (4). In our previous study, healthy subjects with the FOXO3 SNP rs12212067 had lower IFN-g production in peripheral NK cells after 18 h of R848 stimulation (7). Furthermore two of the here analysed SNPs (rs2802292, rs12206094) are associated with longevity (2,3).…”

Section: Discussionsupporting

confidence: 51%

“…SNPs in FOXO3 were shown in previous studies to be associated with ameliorated clinical course of rheumatoid arthritis (30), Crohn´s disease (4) and viral myocarditis (7). In the study by Lee et al monocytes from healthy subjects carrying the SNP rs12212067 had lower TNF-a response upon LPS stimulation (4).…”

Section: Discussionmentioning

confidence: 94%

“…A role of FOXO3 in dampening immune reactions was discussed in several studies (5,6). We showed that Foxo3 plays an important role in acute viral infection as its activation attenuated natural killer (NK) cell responses in a viral myocarditis model (7). Thus, FOXO3 modulation would have therapeutic potential in chronic and autoimmune diseases.…”

Section: Introductionmentioning

confidence: 96%

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Metformin Attenuates ROS via FOXO3 Activation in Immune Cells

et al. 2021

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Forkhead box O 3 (FOXO3) is a transcription factor involved in cell metabolism, inflammation and longevity. Here, we investigated if metformin can activate FOXO3 in human immune cells and affects the subsequent level of reactive oxygen/nitrogen species (ROS/RNS) in immune cells. AMP-activated protein kinase (AMPK) and FOXO3 activation were investigated by immunoblot or flow cytometry (FC) analysis, respectively. FOXO3 target gene expression was quantified by real-time PCR. ROS/RNS measurement using dichlorodihydrofluorescein diacetate (DCFH-DA) dye was investigated by FC. The role of the FOXO3 single nucleotide polymorphisms (SNPs) rs12212067, rs2802292 and rs12206094 on ROS/RNS production was studied using allelic discrimination PCR. Metformin induced activation of AMPK (pT172) and FOXO3 (pS413). ROS/RNS level was reduced in immune cells after metformin stimulation accompanied by induction of the FOXO3 targets mitochondrial superoxide dismutase and cytochrome c. Studies in Foxo3 deficient (Foxo3-/-) mouse splenocytes confirmed that metformin mediates its effects via Foxo3 as it attenuates ROS/RNS in myeloid cells of wildtype (WT) but not of Foxo3-/- mice. Our results suggest that FOXO3 can be activated by metformin leading to reduced ROS/RNS level in immune cells. This may add to the beneficial clinical effects of metformin observed in large cohort studies on longevity, cardiovascular and cancer risk.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 96%

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Metformin Attenuates ROS via FOXO3 Activation in Immune Cells

et al. 2021

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“…В патогенезе миокардита/воспалительной КМП и перипартальной КМП генетическая предрасположенность наряду с аутоиммунными и воспалительными факторами также играет значительную роль. Так, в ряде исследований обнаружено, что полиморфизм rs12212067 гена FOXO3 ассоциирован с вирусно-воспалительной кардиомиопатией, а мутации в гене TTN, детерминирующие развитие перипартальной кардиомиопатии, ассоциированы с семейной ДКМП, не диагностированной ранее [56,57].…”

Section: Discussionunclassified

Dilated cardiomyopathy: reconceptualization of the problem

et al. 2019

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Dilated cardiomyopathy (DCM) is a complex, etiologically heterogeneous myocardial disease, which is one of the main causes of heart failure and heart transplantation. In 2016, experts from the European working group proposed a new definition of cardiomyopathy, which includes intermediate variants with a change in phenotype in carriers of mutations from subclinical form to the full manifestations of the disease. The classification of DCM was supplemented with intermediate phenotypes with the inclusion of a hypokinetic form with reduced contractile function without ventricular dilatation and variants with predominant dilation or arrhythmogenicity. Pathological architectonics of DCM consists of many genetic determinants that interact with numerous environmental factors. Clinical manifestations depend not only on the malignancy and penetrance of the gene mutation, but also on a number of other causes — epigenomic factors, age, toxic effects, environmental aggressiveness, pregnancy, and the effects of other acquired diseases. The article summarizes the current epidemiological data and ideas about specific molecular changes with an unfavorable prognosis. For clarity, we present clinical observations of familial DCM with mutations in the RBM20 and LMNA genes.

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“…FoxO3a has been implicated in CVD pathology yet the mechanism through which FoxO3 may exacerbate or ameliorate CVD is currently unknown. FoxO3 has been proposed to modulate cell proliferation and cell death pathways [ 202 , 203 , 204 ]. Overexpression of FoxO3a was shown to increase gene expression of the cell cycle-dependent kinase inhibitor (CdkI) p27 (Kip1), resulting in cell cycle arrest and attenuation of growth in VSMCs and muscle precursor cells [ 205 , 206 ].…”

Section: Foxo Transcriptional Signalingmentioning

confidence: 99%

Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth

Holland

Francisco

Johnson

et al. 2018

JCDD

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Cardiovascular disease (CVD), including myocardial infarction (MI) and peripheral or coronary artery disease (PAD, CAD), remains the number one killer of individuals in the United States and worldwide, accounting for nearly 18 million (>30%) global deaths annually. Despite considerable basic science and clinical investigation aimed at identifying key etiologic components of and potential therapeutic targets for CVD, the number of individuals afflicted with these dreaded diseases continues to rise. Of the many biochemical, molecular, and cellular elements and processes characterized to date that have potential to control foundational facets of CVD, the multifaceted cyclic nucleotide pathways continue to be of primary basic science and clinical interest. Cyclic adenosine monophosphate (cyclic AMP) and cyclic guanosine monophosphate (cyclic GMP) and their plethora of downstream protein kinase effectors serve ubiquitous roles not only in cardiovascular homeostasis but also in the pathogenesis of CVD. Already a major target for clinical pharmacotherapy for CVD as well as other pathologies, novel and potentially clinically appealing actions of cyclic nucleotides and their downstream targets are still being discovered. With this in mind, this review article focuses on our current state of knowledge of the cyclic nucleotide-driven serine (Ser)/threonine (Thr) protein kinases in CVD with particular emphasis on cyclic AMP-dependent protein kinase (PKA) and cyclic GMP-dependent protein kinase (PKG). Attention is given to the regulatory interactions of these kinases with inflammatory components including interleukin 6 signals, with G protein-coupled receptor and growth factor signals, and with growth and synthetic transcriptional platforms underlying CVD pathogenesis. This article concludes with a brief discussion of potential future directions and highlights the importance for continued basic science and clinical study of cyclic nucleotide-directed protein kinases as emerging and crucial controllers of cardiac and vascular disease pathologies.

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The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis

Cited by 24 publications

References 204 publications

Metformin Attenuates ROS via FOXO3 Activation in Immune Cells

Metformin Attenuates ROS via FOXO3 Activation in Immune Cells

Dilated cardiomyopathy: reconceptualization of the problem

Cyclic Nucleotide-Directed Protein Kinases in Cardiovascular Inflammation and Growth

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