Περίληψη:
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.
Συγγραφείς:
Hitzel, Juliane
Lee, Eunjee
Zhang, Yi
Bibli, Sofia Iris and
Li, Xiaogang
Zukunft, Sven
Pflueger, Beatrice
Hu, Jiong and
Schuermann, Christoph
Vasconez, Andrea Estefania
Oo, James A.
and Kratzer, Adelheid
Kumar, Sandeep
Rezende, Flavia and
Josipovic, Ivana
Thomas, Dominique
Giral, Hector
Schreiber,
Yannick
Geisslinger, Gerd
Fork, Christian
Yang, Xia and
Sigala, Fragiska
Romanoski, Casey E.
Kroll, Jens
Jo,
Hanjoong
Landmesser, Ulf
Lusis, Aldons J.
Namgaladze, Dmitry
and Fleming, Ingrid
Leisegang, Matthias S.
Zhu, Jun
Brandes,
Ralf P.
