Abstract

Oxidized phospholipids (oxPAPC) induce endothelial dysfunction and atherosclerosis. Here we show that oxPAPC induce a gene network regulating serine-glycine metabolism with the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) as a causal regulator using integrative network modeling and Bayesian network analysis in human aortic endothelial cells. The cluster is activated in human plaque material and by atherogenic lipoproteins isolated from plasma of patients with coronary artery disease (CAD). Single nucleotide polymorphisms (SNPs) within the MTHFD2-controlled cluster associate with CAD. The MTHFD2-controlled cluster redirects metabolism to glycine synthesis to replenish purine nucleotides. Since endothelial cells secrete purines in response to oxPAPC, the MTHFD2-controlled response maintains endothelial ATP. Accordingly, MTHFD2-dependent glycine synthesis is a prerequisite for angiogenesis. Thus, we propose that endothelial cells undergo MTHFD2-mediated reprogramming toward serine-glycine and mitochondrial one-carbon metabolism to compensate for the loss of ATP in response to oxPAPC during atherosclerosis.

Details

Title
Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells
Author
Hitzel, Juliane 1 ; Lee, Eunjee 2 ; Zhang, Yi 3   VIAFID ORCID Logo  ; Bibli, Sofia Iris 4 ; Li, Xiaogang 5 ; Zukunft, Sven 4   VIAFID ORCID Logo  ; Pflüger, Beatrice 1 ; Hu, Jiong 4 ; Schürmann, Christoph 1 ; Vasconez, Andrea Estefania 1 ; Oo, James A 1 ; Kratzer, Adelheid 6 ; Kumar, Sandeep 7   VIAFID ORCID Logo  ; Rezende, Flávia 1 ; Josipovic, Ivana 1 ; Thomas, Dominique 8 ; Giral, Hector 6 ; Schreiber, Yannick 9 ; Geisslinger, Gerd 10 ; Fork, Christian 1 ; Yang, Xia 11 ; Sigala, Fragiska 12 ; Romanoski, Casey E 13 ; Kroll, Jens 5 ; Hanjoong Jo 7   VIAFID ORCID Logo  ; Landmesser, Ulf 14 ; Lusis, Aldons J 15 ; Namgaladze, Dmitry 16 ; Fleming, Ingrid 4 ; Leisegang, Matthias S 1 ; Zhu, Jun 2   VIAFID ORCID Logo  ; Brandes, Ralf P 1 

1  Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany; German Center for Cardiovascular Research (DZHK) (Partner site Rhine-Main), Frankfurt am Main, Germany 
2  Icahn Institute of Genomics and Multiscale Biology, Mount Sinai Icahn School of Medicine, New York, NY, USA; Sema4 Genomics (a Mount Sinai venture), Stamford, CT, USA 
3  Icahn Institute of Genomics and Multiscale Biology, Mount Sinai Icahn School of Medicine, New York, NY, USA; Department of Mathematics, Hebei University of Science and Technology, Shijiazhuang, Hebei, China 
4  German Center for Cardiovascular Research (DZHK) (Partner site Rhine-Main), Frankfurt am Main, Germany; Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany 
5  Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany 
6  Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; German Center for Cardiovascular Research (DZHK) (Partner site Berlin), Berlin, Germany 
7  Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA 
8  Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany 
9  Fraunhofer Institute of Molecular Biology and Applied Ecology—Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany 
10  Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Faculty of Medicine, Goethe University, Frankfurt am Main, Germany; Fraunhofer Institute of Molecular Biology and Applied Ecology—Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany 
11  Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA 
12  1st Department of Propaedeutic Surgery, University of Athens Medical School, Hippocration Hospital, Athens, Greece 
13  Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA 
14  Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; German Center for Cardiovascular Research (DZHK) (Partner site Berlin), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany 
15  Departments of Medicine, Microbiology and Human Genetics, University of California, Los Angeles, CA, USA 
16  Institute of Biochemistry I, Goethe University, Frankfurt am Main, Germany 
Pages
1-18
Publication year
2018
Publication date
Jun 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04602-0
ProQuest document ID
2054060019
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.