title: Pharmacological inhibition of arginine and lysine methyltransferases induces nuclear abnormalities and suppresses angiogenesis in human endothelial cells.
abstract: Posttranslational modifications of histone tails can alter chromatin structure and regulate gene transcription. While recent studies implicate the lysine/arginine protein methyltransferases in the regulation of genes for endothelial metabolism, the role of AMI-1 and AMI-5 compounds in angiogenesis remains unknown. Here, we show that global inhibition of arginine and lysine histone methyltransferases (HMTs) by AMI-5 induced an angiostatic profile in human microvascular endothelial cells and human umbilical vein endothelial cells. Based on FACS analysis, we found that inhibition of HMTs significantly affects proliferation of endothelial cells, by suppressing cell cycle progression in the G0/G1phase. Immunofluorescent studies of the endothelial cells replication pattern by 5-ethynyl-2'-deoxyuridine incorporation disclosed that AMI-5, and the arginine methyltransferase inhibitor AMI-1, induced heterochromatin formation and a number of nuclear abnormalities, such as formation of micronuclei (MNs) and nucleoplasmic bridges (NPBs), which are markers of chromosomal instability. In addition to the modification of the cell cycle machinery in response to AMIs treatment, also endothelial cells migration and capillary-like tube formation processes were significantly inhibited, implicating a stimulatory role of HMTs in angiogenesis.
authors.affiliation: Department of Molecular Biophysics, University of Lodz, Poland. Electronic address: abal@biol.uni.lodz.pl.
authors.forename: Aneta
authors.initials: A
authors.lastname: Balcerczyk
authors.affiliation: Department of Cytophysiology, University of Lodz, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Rybaczek
authors.affiliation: Department of Molecular Biophysics, University of Lodz, Poland.
authors.forename: Martyna
authors.initials: M
authors.lastname: Wojtala
authors.affiliation: Faculty of Medicine, INSERM U1060, Lyon, France.
authors.forename: Luciano
authors.initials: L
authors.lastname: Pirola
authors.affiliation: Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart & Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.
authors.forename: Jun
authors.initials: J
authors.lastname: Okabe
authors.affiliation: Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart & Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Epigenomics Profiling Facility, Baker IDI Heart & Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; Central Clinical School, Faculty of Medicine, Monash University, Victoria, Australia.
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006570:Heterochromatin / Q000187:drug effects / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D009282:Naphthalenesulfonates / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000517:prevention & control; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: C000619251:2-(2,4,5,7-tetrabromo-3-oxido-6-oxoxanthen-9-yl)benzoate; C535077:7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid; D020533:Angiogenesis Inhibitors; D001565:Benzoates; D006570:Heterochromatin; D009282:Naphthalenesulfonates; D014966:Xanthenes; D014508:Urea; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: Angiogenesis process; Arginine/lysine histone methyltransferases; Endothelial cells