Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells

• Type of Material: Article
• Authors: Juliane Hitzel, Goethe University; Eunjee Lee, Mount Sinai Icahn School of Medicine; Yi Zhang, Mount Sinai Icahn School of Medicine; Sofia Bibli, German Center for Cardiovascular Research (DZHK); Xiaogang Li, Heidelberg University; Sven Zukunft, German Center for Cardiovascular Research (DZHK); Beatrice Pflueger, Goethe University; Jiong Hu, German Center for Cardiovascular Research (DZHK); Christoph Schuermann, Goethe University; Andrea Estefania Vasconez, Goethe University; James A. Oo, Goethe University; Adelheid Kratzer, Charité-Universitätsmedizin Berlin; Sandeep Kumar, Emory University; Flavia Rezende, Goethe University; Ivana Josipovic, Goethe University; Dominique Thomas, Goethe University; Hector Giral, Charité-Universitätsmedizin Berlin; Yannick Schreiber, Fraunhofer Institute of Molecular Biology and Applied Ecology—Project Group Translational Medicine and Pharmacology (IME-TMP); Gerd Geisslinger, Goethe University; Christian Fork, Goethe University; Xia Yang, University of California Los Angeles; Fragiska Sigala, University of Athens; Casey E. Romanoski, University of Arizona; Jens Kroll, Heidelberg University; Hanjoong Jo, Emory University; Ulf Landmesser, Charité-Universitätsmedizin Berlin; Aldons J. Lusis, University of California Los Angeles; Dmitry Namgaladze, Goethe University; Ingrid Fleming, German Center for Cardiovascular Research (DZHK) (Partner site Rhine-Main); Matthias S. Leisegang, Goethe University; Jun Zhu, Mount Sinai Icahn School of Medicine; Ralf P. Brandes, Goethe University
• Language: English
• Date: 2018-06-12
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-04602-0
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 2292
• End Page: 2292
• Grant/Funding Information: Computational analyses were funded by NIH grant U01HG008451.; This study was supported by the DFG Excellence Cluster “Cardiopulmonary System—ECCPS”, the SFB 1039, IRTG1874/2 DIAMICOM, the SFB 1118, German Center for Cardiovascular Research DZHK and the Faculty of Medicine, Goethe University, Frankfurt am Main, Germany.; Partial carotid ligation studies were supported by US National Institutes of Health grant HL095070.; Generation of the HAEC transcription data sets underlying the networks was funded by US National Institutes of Health grant HL30568.
• Keywords: CANCER-CELLS; ATHEROSCLEROSIS; UNFOLDED PROTEIN RESPONSE; Science & Technology; ER STRESS; CORONARY-ARTERY-DISEASE; Multidisciplinary Sciences; VASCULAR MORPHOGENESIS; NETWORKS; GENE-EXPRESSION; SEGREGATING POPULATIONS; Science & Technology - Other Topics; ATP RELEASE
• Research Categories: Health Sciences, Medicine and Surgery

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.