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

  • 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.
Author:Juliane Hitzel, Eunjee Lee, Yi ZhangORCiD, Sofia Iris Bibli, Xiaogang Li, Sven ZukunftORCiD, Beatrice Pflüger, Jiong Hu, Christoph Schürmann, Andrea Estefania Vasconez, James A. OoORCiDGND, Adelheid Kratzer, Sandeep KumarORCiD, Flávia Figueiredo de Rezende FelipeORCiDGND, Ivana Josipovic, Dominique Jeanette ThomasORCiDGND, Hector Giral, Yannick Schreiber, Gerd GeisslingerORCiDGND, Christian Fork, Xia Yang, Fragiska Sigala, Casey E. Romanoski, Jens Kroll, Hanjoong JoORCiD, Ulf Landmesser, Aldons J. Lusis, Dmitry Namgaladze, Ingrid FlemingORCiD, Matthias LeisegangORCiDGND, Jianhui ZhuORCiD, Ralf Peter Louis BrandesORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29895827
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/06/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/06/19
Tag:Atherosclerosis; Bayesian inference; Phospholipids; Regulatory networks
Issue:1, Art. 2292
Page Number:18
First Page:1
Last Page:18
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Institutes:Medizin / Medizin
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0