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

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.

• Authors: 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, Ralf P Brandes
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 2292 (06 12 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29895827 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• MTHFD2 protein, human
• Multifunctional Enzymes
• Nucleotides
• Phospholipids
• Purines
• RNA, Small Interfering
• Methylenetetrahydrofolate Dehydrogenase (NADP)
• Aminohydrolases
• Oxygen
• Glycine

Topics

• Amino Acids (metabolism)
• Aminohydrolases (metabolism)
• Animals
• Aorta (cytology)
• Atherosclerosis (metabolism)
• Bayes Theorem
• Cardiovascular Diseases (metabolism)
• Endothelial Cells (metabolism)
• Gene Expression Regulation
• Genetic Techniques
• Glycine (chemistry)
• Human Umbilical Vein Endothelial Cells
• Humans
• Methylenetetrahydrofolate Dehydrogenase (NADP) (metabolism)
• Multifunctional Enzymes (metabolism)
• Multigene Family
• Neovascularization, Pathologic
• Nucleotides (chemistry)
• Oxygen (chemistry)
• Phospholipids (chemistry)
• Probability
• Purines (chemistry)
• RNA, Small Interfering (metabolism)
• Zebrafish