title: FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in human endothelial cells and subjects with atherosclerosis.
abstract: OBJECTIVE
  The O subfamily of forkhead (FoxO) 1 is a pivotal element in the regulation of endothelial activation. Compartmentalization and activity of FoxO1 is regulated by post translational modifications, but the implication in endothelial dysfunction and atherosclerosis remain controversial. Our aim was to identify FoxO1 related metabolic signatures in endothelial cells.
  
  
  RESULTS
  Using metabolomics in human umbilical endothelial cells (HUVECs) overexpressing the wild type FoxO1 (FoxO1-WT), the acetylation defective mutant (FoxO1-KR), the unphosphorylated nuclear localized mutant (FoxO1-ADA) and the Green Fluorescent Protein (GFP) control vector, we identify metabolic pathways differentially affected by the different FoxO1 localization and activity. Among metabolites, asymmetric dimethylarginine (ADMA) was increased in FoxO1-ADA compared with FoxO1-WT and FoxO1-KR infected cells (p < 0.01). ADMA was further investigated to identify the molecular mechanisms to explain its link to FoxO1. We found that unrestrained FoxO1 activity leads to increase of ADMA via downregulation of its degrading enzyme, dimethylaminohydrolase (DDAH) 1. In human subjects (n = 89) the FoxO1/DDAH1/ADMA pathway marks unstable atherosclerosis.
  
  
  CONCLUSIONS
  Our results point to ADMA as a biomarker to track deregulated FoxO1 activity in vivo.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy. Electronic address: menghini@med.uniroma2.it.
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Casagrande
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Cardellini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Ballanti
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Davato
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Iris
authors.initials: I
authors.lastname: Cardolini
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Fabrizi
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Morelli
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Anemona
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Bernges
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Ippoliti
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauriello
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Center for Atherosclerosis, Policlinico Tor Vergata, 00133 Rome, Italy. Electronic address: federicm@uniroma2.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000201:enzymology* / Q000235:genetics; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D015536:Down-Regulation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D015971:Gene Expression Regulation, Enzymologic; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D055432:Metabolomics / Q000379:methods; D009154:Mutation; D015398:Signal Transduction; D014162:Transfection
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: ADMA; Atherosclerosis; Biomarker; Endothelium; FoxO1