Oberle S, Polte T, Abate A, Podhaisky H P, Schröder H
Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle (Saale), Germany.
Circ Res. 1998 May 18;82(9):1016-20. doi: 10.1161/01.res.82.9.1016.
Aspirin has recently been shown to increase endothelial resistance to oxidative damage. However, the mechanism underlying aspirin-induced cytoprotection is still unknown. Using cultured cells, the present study investigates the effect of aspirin on the expression of ferritin, a cytoprotective protein that sequesters free cytosolic iron, the main catalyst of oxygen radical formation. In bovine pulmonary artery endothelial cells, aspirin at low antithrombotic concentrations (0.03 to 0.3 mmol/L) induced the synthesis of ferritin protein in a time- and concentration-dependent fashion up to 5-fold over basal levels, whereas ferritin H (heavy chain) mRNA remained unaltered. Aspirin-induced cytoprotection from hydrogen peroxide toxicity was mimicked by exogenous iron-free apoferritin but not iron-loaded ferritin, demonstrating the antioxidant function of newly synthesized ferritin under these conditions. Ferritin induction by aspirin was specific in that other nonsteroidal anti-inflammatory drugs such as salicylic acid, indomethacin, or diclofenac failed to alter ferritin protein levels. Aspirin-induced ferritin synthesis was abrogated in the presence of the iron chelator desferrioxamine, pointing to an interaction of aspirin with iron-responsive activation of ferritin translation. Together, our results suggest induction of ferritin as a novel mechanism by which aspirin may prevent endothelial injury in cardiovascular disease, eg, during atherogenesis.
最近研究表明，阿司匹林可增强内皮细胞对氧化损伤的耐受性。然而，阿司匹林诱导细胞保护作用的机制尚不清楚。本研究利用培养细胞，探讨阿司匹林对铁蛋白表达的影响，铁蛋白是一种细胞保护蛋白，可螯合游离的胞质铁，而胞质铁是氧自由基形成的主要催化剂。在牛肺动脉内皮细胞中，低抗血栓浓度（0.03至0.3 mmol/L）的阿司匹林以时间和浓度依赖的方式诱导铁蛋白合成，最高可达基础水平的5倍，而铁蛋白H（重链）mRNA水平未发生改变。外源性无铁脱铁铁蛋白可模拟阿司匹林诱导的对过氧化氢毒性的细胞保护作用，而含铁铁蛋白则不能，这表明在这些条件下新合成的铁蛋白具有抗氧化功能。阿司匹林对铁蛋白的诱导具有特异性，因为其他非甾体抗炎药如水杨酸、吲哚美辛或双氯芬酸均未能改变铁蛋白蛋白水平。在铁螯合剂去铁胺存在的情况下，阿司匹林诱导的铁蛋白合成被消除，这表明阿司匹林与铁蛋白翻译的铁反应性激活存在相互作用。总之，我们的结果表明，铁蛋白的诱导是阿司匹林预防心血管疾病（如动脉粥样硬化形成过程中）内皮损伤的一种新机制。
