A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia.
A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia.
复制标题
DOI：
10.1016/j.bbrc.2009.10.067
复制
发表时间：
2009-12-25
影响因子：
3.1
通讯作者：
Majetschak, Matthias
中科院分区：
文献类型：
--
作者：
Geng, Qing;Romero, Jacqueline;Saini, Vikas;Baker, Todd A.;Picken, Maria M.;Gamelli, Richard L.;Majetschak, Matthias
热缺血或冷缺血时心肌损伤的分子机制尚不清楚。虽然蛋白酶体被认为是心肌缺血-再灌注损伤的一个重要因素，但其在缺血期间的作用仍不清楚。由于供体心脏通常暴露于长期的全球冷缺血心脏移植前，我们评估的作用和调节的蛋白酶体在大鼠心脏的心肌ATP含量的背景下冷缺血存储。在威斯康星州大学（UW）溶液中冷缺血保存心脏48 h，当ATP浓度降低时，心脏蛋白酶体肽酶活性增加225%。在UW溶液中加入特异性蛋白酶体抑制剂epoxomicin可抑制心脏提取物中的蛋白酶体活性，显著减少水肿形成，并保持心肌细胞超微结构的完整性。利用纯化的20 S/26 S蛋白酶体酶制剂，我们证明，这种激活可以归因于一个子集的26 S蛋白酶体，这是稳定的ATP浓度远低于生理水平，ATP负调节其活性和最大的激活发生在低mol/L范围内的ATP浓度。这些数据表明，蛋白酶体激活是冷缺血心肌损伤的病理生理相关机制。26 S蛋白酶体的一个子集似乎是一种细胞破坏性蛋白酶，随着ATP水平下降而被激活。冷缺血期间蛋白酶体抑制可保持心肌细胞超微结构的完整性。
Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low mol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte.
登录
查看更多内容
影响因子：
16.6
作者：
Finley D
通讯作者：
Finley D
影响因子：
4.8
作者：
Bulteau, AL;Lundberg, KC;Szweda, LI
通讯作者：
Szweda, LI
影响因子：
64.5
作者：
Babbitt, SE;Kiss, A;Skowyra, D
通讯作者：
Skowyra, D
影响因子：
5
作者：
Powell, Saul R.;Davies, Kelvin J. A.;Divald, Andras
通讯作者：
Divald, Andras
影响因子：
5
作者：
Campbell, B;Adams, J;Lefer, AM
通讯作者：
Lefer, AM