Aldose reductase induced by hyperosmotic stress mediates cardiomyocyte apoptosis - Differential effects of sorbitol and mannitol
Aldose reductase induced by hyperosmotic stress mediates cardiomyocyte apoptosis - Differential effects of sorbitol and mannitol
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DOI：
10.1074/jbc.m211824200
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发表时间：
2003-10-03
影响因子：
4.8
通讯作者：
Lavandero, S
中科院分区：
文献类型：
--
作者：
Galvez, AS;Ulloa, JA;Lavandero, S
细胞通过几种机制适应高渗条件，包括通过诱导多元醇途径积累山梨醇。不能适应渗透胁迫可导致凋亡性细胞死亡。在本研究中，我们评估的作用，醛糖还原酶，多元醇途径的关键酶，在心肌细胞凋亡。高渗应激，引起暴露培养的大鼠心肌细胞的非渗透性溶质山梨醇和甘露醇，引起相同的细胞收缩和自适应己糖摄取刺激。相反，只有山梨糖醇诱导多元醇途径和触发应激途径以及与脱水相关的信号传导事件。山梨糖醇导致细胞外信号调节激酶（ERK）、p54 c-Jun N-末端激酶（JNK）和蛋白激酶B活化。此外，山梨醇治疗导致诱导和激活的醛糖还原酶，抗凋亡蛋白Bcl-xL的表达减少，增加DNA片段化，谷胱甘肽耗尽。通过佐泊司他抑制醛糖还原酶以及N-乙酰半胱氨酸补充谷胱甘肽，可减弱细胞凋亡。总之，我们的数据表明，单独的心肌细胞高渗收缩不足以诱导心肌细胞凋亡。高渗透压诱导的细胞死亡对渗压剂的性质敏感，并且需要醛糖还原酶的诱导以及细胞内谷胱甘肽水平的降低。
Cells adapt to hyperosmotic conditions by several mechanisms, including accumulation of sorbitol via induction of the polyol pathway. Failure to adapt to osmotic stress can result in apoptotic cell death. In the present study, we assessed the role of aldose reductase, the key enzyme of the polyol pathway, in cardiac myocyte apoptosis. Hyperosmotic stress, elicited by exposure of cultured rat cardiac myocytes to the nonpermeant solutes sorbitol and mannitol, caused identical cell shrinkage and adaptive hexose uptake stimulation. In contrast, only sorbitol induced the polyol pathway and triggered stress pathways as well as apoptosis-related signaling events. Sorbitol resulted in activation of the extracellular signal-regulated kinase (ERK), p54 c-Jun N-terminal kinase (JNK), and protein kinase B. Furthermore, sorbitol treatment resulting in induction and activation of aldose reductase, decreased expression of the antiapoptotic protein Bcl-xL, increased DNA fragmentation, and glutathione depletion. Apoptosis was attenuated by aldose reductase inhibition with zopolrestat and also by glutathione replenishment with N-acetylcysteine. In conclusion, our data show that hypertonic shrinkage of cardiac myocytes alone is not sufficient to induce cardiac myocyte apoptosis. Hyperosmolarity-induced cell death is sensitive to the nature of the osmolyte and requires induction of aldose reductase as well as a decrease in intracellular glutathione levels.