Bode-Böger Stefanie M, Scalera Fortunato, Martens-Lobenhoffer Jens
Institute of Clinical Pharmacology, University Hospital Otto-von-Guericke University, Magdeburg, Germany.
Vasc Med. 2005 Jul;10 Suppl 1:S65-71. doi: 10.1177/1358836X0501000110.
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.
不对称二甲基精氨酸（ADMA）是一氧化氮合酶的内源性抑制剂，其蓄积与心血管疾病相关。我们旨在研究ADMA在内皮细胞衰老中的作用。将内皮细胞培养至第10代。从第4代开始，每48小时更换一次ADMA。ADMA显著加速衰老相关的β-半乳糖苷酶活性。此外，端粒长度的缩短显著加快，端粒酶活性显著降低。这种效应与氧化应激增加有关：与对照组相比，ADMA处理后，作为氧自由基生成标志物的尿囊素和细胞内活性氧均显著增加，而一氧化氮合成减少。此外，ADMA增加的氧化应激伴随着降解ADMA的二甲基精氨酸二甲胺水解酶活性降低，抗氧化剂吡咯烷二硫代氨基甲酸盐可预防这种降低。外源性ADMA还刺激单核细胞趋化蛋白-1和白细胞介素-8的分泌。与甲基转移酶抑制剂S-腺苷同型半胱氨酸共同孵育可消除ADMA的作用。这些数据表明，ADMA可能通过抑制一氧化氮生成增加氧自由基形成来加速衰老。本研究提供了证据，即细胞内ADMA水平的适度变化与对减缓内皮细胞衰老的显著影响相关。
