title: Asymmetric dimethylarginine (ADMA) accelerates cell senescence.
abstract: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and its accumulation has been associated with cardiovascular disease. We aimed to investigate the role of ADMA in endothelial cell senescence. Endothelial cells were cultured until the tenth passage. ADMA was replaced every 48 hours starting at the fourth passage. ADMA significantly accelerated senescence-associated beta-galactosidase activity. Additionally, the shortening of telomere length was significantly speeded up and telomerase activity was significantly reduced. This effect was associated with an increase of oxidative stress: both allantoin, a marker of oxygen free radical generation, and intracellular reactive oxygen species increased significantly after ADMA treatment compared with control, whereas nitric oxide synthesis decreased. Furthermore, ADMA-increased oxidative stress was accompanied by a decrease in the activity of dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA, which could be prevented by the antioxidant pyrrolidine dithiocarbamate. Exogenous ADMA also stimulated secretion of monocyte chemotactic protein-1 and interleukin-8. Co-incubation with the methyltransferase inhibitor S-adenosylhomocysteine abolished the effects of ADMA. These data suggest that ADMA accelerates senescence, probably via increased oxygen radical formation by inhibiting nitric oxide elaboration. This study provides evidence that modest changes of intracellular ADMA levels are associated with significant effects on slowing down endothelial senescence.
authors.affiliation: Institute of Clinical Pharmacology, University Hospital Otto-von-Guericke University, Magdeburg, Germany. stefanie.bode-boeger@medizin.uni-magdeburg.de
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Bode-Böger
authors.forename: Fortunato
authors.initials: F
authors.lastname: Scalera
authors.forename: Jens
authors.initials: J
authors.lastname: Martens-Lobenhoffer
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence; D018932:Chemokine CCL2; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000494:pharmacology; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D017382:Reactive Oxygen Species; C018524:N,N-dimethylarginine; D001120:Arginine; D012435:S-Adenosylhomocysteine; D019001:Nitric Oxide Synthase; D019098:Telomerase; D000581:Amidohydrolases; C059999:dimethylargininase