Bode-Böger Stefanie M, Martens-Lobenhoffer Jens, Täger Michael, Schröder Henning, Scalera Fortunato
Institute of Clinical Pharmacology, University Hospital, Otto-von-Guericke University, Germany.
Biochem Biophys Res Commun. 2005 Sep 9;334(4):1226-32. doi: 10.1016/j.bbrc.2005.07.014.
We report here the effect of aspirin on the onset of replicative senescence. Endothelial cells that were cultured until cumulative population doublings 40 showed clear signs of aging. Incubation with aspirin inhibited senescence-associated beta-galactosidase activity and increased telomerase activity. Along with the delayed onset of senescence, aspirin decreased reactive oxygen species and increased nitric oxide (NO) and cGMP levels. Furthermore, aspirin reduced the elaboration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and up-regulated the activity of dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA. These effects were specific in that other nonsteroidal anti-inflammatory drugs, such as ibuprofen or acetaminophen, did not prevent the onset of endothelial senescence. The NO synthase inhibitor l-NAME, but not its inactive d-enantiomer, led to complete inhibition of aspirin-delayed senescence. These findings demonstrate that aspirin delays the onset of endothelial senescence by preventing a decrease in NO formation/generation. This might provide a therapeutic strategy aimed at blocking aging-induced NO inhibition.
我们在此报告阿司匹林对复制性衰老起始的影响。培养至累积群体倍增数达40的内皮细胞显示出明显的衰老迹象。用阿司匹林孵育可抑制衰老相关的β-半乳糖苷酶活性并增加端粒酶活性。随着衰老起始的延迟，阿司匹林降低了活性氧水平，并提高了一氧化氮（NO）和环磷酸鸟苷（cGMP）水平。此外，阿司匹林减少了不对称二甲基精氨酸（ADMA，一种NO合酶的内源性抑制剂）的生成，并上调了二甲基精氨酸二甲胺水解酶（降解ADMA的酶）的活性。这些作用具有特异性，因为其他非甾体抗炎药，如布洛芬或对乙酰氨基酚，并不能阻止内皮细胞衰老的起始。NO合酶抑制剂L-NAME（而非其无活性的d-对映体）可导致阿司匹林延迟的衰老完全受到抑制。这些发现表明，阿司匹林通过防止NO生成/产生的减少来延迟内皮细胞衰老的起始。这可能提供一种旨在阻止衰老诱导的NO抑制的治疗策略。
