FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in human endothelial cells and subjects with atherosclerosis.

Abstract

BACKGROUND AND AIMS:

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.

METHODS AND 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: Rossella Menghini, Viviana Casagrande, Marina Cardellini, Marta Ballanti, Francesca Davato, Iris Cardolini, Robert Stoehr, Marta Fabrizi, Monica Morelli, Lucia Anemona, Isabel Bernges, Edzard Schwedhelm, Arnaldo Ippoliti, Alessandro Mauriello, Rainer H Böger, Massimo Federici
• Journal: Atherosclerosis (Atherosclerosis) Vol. 242 Issue 1 Pg. 230-5 (Sep 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 26226438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• N,N-dimethylarginine
• Arginine
• Amidohydrolases
• dimethylargininase

Topics

• Amidohydrolases (metabolism)
• Arginine (analogs & derivatives, metabolism)
• Carotid Artery Diseases (enzymology, genetics)
• Cells, Cultured
• Chromatography, Liquid
• Down-Regulation
• Forkhead Box Protein O1
• Forkhead Transcription Factors (genetics, metabolism)
• Gas Chromatography-Mass Spectrometry
• Gene Expression Regulation, Enzymologic
• Human Umbilical Vein Endothelial Cells (enzymology)
• Humans
• Metabolomics (methods)
• Mutation
• Signal Transduction
• Transfection