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

Juliane Hitzel, Eunjee Lee, Yi Zhang, Sofia Iris Bibli, Xiaogang Li, Sven Zukunft, Beatrice Pflüger, Jiong Hu, Christoph Schürmann, Andrea Estefania Vasconez, James A. Oo, Adelheid Kratzer, Sandeep Kumar, Flávia Rezende, Ivana Josipovic, Dominique Thomas, Hector Giral, Yannick Schreiber, Gerd Geisslinger, Christian Fork, Xia Yang, Fragiska Sigala, Casey E. Romanoski, Jens Kroll, Hanjoong Jo, Ulf Landmesser, Aldons J. Lusis, Dmitry Namgaladze, Ingrid Fleming, Matthias S. Leisegang, Jun Zhu () and Ralf P. Brandes ()
Additional contact information
Juliane Hitzel: Goethe University
Eunjee Lee: Mount Sinai Icahn School of Medicine
Yi Zhang: Mount Sinai Icahn School of Medicine
Sofia Iris Bibli: German Center for Cardiovascular Research (DZHK) (Partner site Rhine-Main)
Xiaogang Li: Heidelberg University
Sven Zukunft: German Center for Cardiovascular Research (DZHK) (Partner site Rhine-Main)
Beatrice Pflüger: Goethe University
Jiong Hu: German Center for Cardiovascular Research (DZHK) (Partner site Rhine-Main)
Christoph Schürmann: Goethe University
Andrea Estefania Vasconez: Goethe University
James A. Oo: Goethe University
Adelheid Kratzer: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin
Sandeep Kumar: Georgia Institute of Technology and Emory University
Flávia Rezende: Goethe University
Ivana Josipovic: Goethe University
Dominique Thomas: Goethe University
Hector Giral: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin
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
Fragiska Sigala: Hippocration Hospital
Casey E. Romanoski: University of Arizona
Jens Kroll: Heidelberg University
Hanjoong Jo: Georgia Institute of Technology and Emory University
Ulf Landmesser: Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin
Aldons J. Lusis: University of California
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

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04602-0

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