Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis
Vesnarinone causes oxidative damage by inhibiting catalase function through ceramide action in myeloid cell apoptosis
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DOI：
10.1124/mol.61.3.620
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发表时间：
2002-03-01
影响因子：
3.6
通讯作者：
Okazaki, T
中科院分区：
文献类型：
--
作者：
Kondo, T;Suzuki, Y;Okazaki, T
维司力农是治疗充血性心力衰竭的有效正性肌力药物，但因粒细胞缺乏症的严重副作用而限制了其临床应用。在髓系HL-60细胞中，维司力农以时间和剂量依赖性方式增加促凋亡脂质介质神经酰胺的细胞内含量。同时用细胞可渗透的N-乙酰鞘氨醇（C2-神经酰胺）处理显著增强了维那力酮诱导的细胞凋亡。无论是用维司力农、C2-神经酰胺还是同时用维司力农和C2-神经酰胺处理，都引起通过2 '，7'-二氯荧光素方法测量的活性氧中间体（ROI）产生的显著增加。然而，氧化损伤判断的生产脂质过氧化物和硝基四氮唑蓝还原能力的增强更显着的同时治疗与维司力农和C2-神经酰胺比单独维司力农。此外，维司力农抑制过氧化氢酶的功能，在蛋白质和活性水平，这种抑制作用是协同增强C2-神经酰胺，和维司力农诱导的氧化损伤和凋亡显着抑制HL-60细胞与纯化的过氧化氢酶处理。C2-神经酰胺增强vesnarinone诱导的抑制感兴趣区清除酶过氧化氢酶的蛋白质和活性水平的HL-60细胞，然而，相比之下，vesnarinone不诱导神经酰胺的产生，氧化损伤，或过氧化氢酶耗尽HL-60/ves细胞，其中vesnarinone不能诱导细胞凋亡。综上所述，结果表明，维司力农通过神经酰胺诱导的过氧化氢酶功能抑制增加氧化损伤来诱导骨髓细胞凋亡。
Vesnarinone is an effective inotropic agent for treating congestive heart failure, but its clinical usage is restricted because of the severe side effect of agranulocytosis. In myeloid HL-60 cells, vesnarinone increased the intracellular content of a proapoptotic lipid mediator, ceramide, in a time- and dose-dependent manner. Vesnarinone-Induced apoptosis was significantly enhanced by simultaneous treatment with a cell-permeable N-acetyl sphingosine (C2-ceramide). Treatment with neither vesnarinone, C2-ceramide, nor simultaneously with vesnarinone and C2-ceramide caused a marked increase of reactive oxygen intermediates (ROI) generation measured by the 2',7'-dichlorofluorescin method. However, oxidative damage judged by the production of lipid peroxidates and the nitroblue tetrazolium-reducing ability were enhanced more significantly by simultaneous treatment with vesnarinone and C2-ceramide than by vesnarinone alone. Moreover, vesnarinone inhibited catalase function both at the protein and activity level, and this inhibition was synergistically enhanced by C2-ceramide, and vesnarinone-induced oxidative damage and apoptosis were significantly suppressed by treatment of HL-60 cells with purified catalase. C2-ceramide enhanced vesnarinone-induced inhibition of the ROI-scavenging enzyme catalase at the levels of protein and activity in HL-60 cells; in contrast, however, vesnarinone did not induce ceramide generation, oxidative damage, or catalase depletion in HL-60/ves cells, where vesnarinone could not induce apoptosis. Taken together, the results suggest that vesnarinone induces myeloid cell apoptosis by increasing oxidative damage via ceramide-Induced inhibition of catalase function.