title: Metabolomic analysis revealed the role of DNA methylation in the balance of arachidonic acid metabolism and endothelial activation.
abstract: Arachidonic acid (AA) metabolism plays an important role in vascular homeostasis. We reported that DNA hypomethylation of EPHX2 induced a pro-inflammatory response in vascular endothelial cells (ECs). However, the change in the whole AA metabolism by DNA methylation is still unknown. Using a metabolomic approach, we investigated the effect of DNA methylation on the balance of AA metabolism and the underlying mechanism. ECs were treated with a DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-AZA), and AA metabolic profiles were analyzed. Levels of prostaglandin D2 (PGD2) and thromboxane B2 (TXB2), metabolites in the cyclooxygenase (COX) pathway, were significantly increased by 5-AZA treatment in ECs resulting from the induction of PGD2 synthase (PTGDS) and thromboxane A synthase 1 (TBXAS1) expression by DNA hypomethylation. This phenomenon was also observed in liver and kidney cell lines, indicating a universal mechanism. Pathophysiologically, homocysteine, known to cause DNA demethylation, induced a similar pattern of the change of AA metabolism. Furthermore, 5-AZA activated ECs, as evidenced by the upregulation of adhesion molecules. Indomethacin, a COX inhibitor, reversed the effects of 5-AZA on the levels of PGD2 and TXB2, EC activation and monocyte adhesion. In vivo, the plasma levels of PGD2 and TXB2 and the expression of In vivo PTGDS and TBXAS1 as well as adhesion molecules were increased in the aorta of the mice injected with 5-AZA. In conclusion, using a metabolomic approach, our study uncovered that DNA demethylation increased AA metabolites PGD2 and TXB2 by upregulating the expression of the corresponding enzymes, which might contribute to the DNA hypomethylation-induced endothelial activation.
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Xue
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Jin-Long
authors.initials: JL
authors.lastname: He
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Ya-Jin
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Feng-Xia
authors.initials: FX
authors.lastname: Xue
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Chun-Jiong
authors.initials: CJ
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China. Electronic address: edin2000cn@gmail.com.
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China. Electronic address: zhuyi@tmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D000077209:Decitabine; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis; D007668:Kidney / Q000166:cytology / Q000201:enzymology; D054834:Lipocalins / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008297:Male; D055432:Metabolomics; D051379:Mice; D013930:Thromboxane-A Synthase / Q000096:biosynthesis
chemical_list: D001095:Arachidonic Acids; D054834:Lipocalins; D000077209:Decitabine; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D013930:Thromboxane-A Synthase; D001374:Azacitidine
keywords: Arachidonic acid metabolism; DNA methylation; Endothelial cell; Metabolomics