Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation
Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation
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DOI：
10.1152/ajpheart.01091.2006
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发表时间：
2007-05-01
影响因子：
4.8
通讯作者：
Chatham, John C.
中科院分区：
文献类型：
--
作者：
Fulop, Norbert;Zhang, Zhenghao;Chatham, John C.
我们已经证明，在灌流的心脏中，氨基葡萄糖促进了缺血后的功能恢复，这似乎是通过增加核质蛋白上O-连接的N-乙酰氨基葡萄糖(O-GlcNAc)水平来实现的。一些激酶通路，特别是Akt和丝裂原活化蛋白激酶(MAPKs)p38和ERK1/2，被认为与缺血性心脏保护有关，也被报道随着O-GlcNAc水平的增加而被修饰。因此，本研究的目的是确定缺血对O-GlcNAc水平的影响，并评估氨基葡萄糖对心肌的保护作用是否归因于ERK1/2、Akt和p38磷酸化的变化。大鼠离体心分别灌流或不灌流5 mM氨基葡萄糖，分别进行5、10、30min低流量缺血或30min低流量缺血+60min再灌流。氨基葡萄糖治疗可减轻缺血肌挛缩，改善再灌流结束时的功能恢复。氨基葡萄糖处理增加了通过己糖胺生物合成途径的通量，增加了O-GlcNAc水平，但对ATP水平没有影响。氨基葡萄糖不改变ERK1/2或Akt对缺血再灌注的反应，但显著减弱缺血诱导的p38磷酸化增加，并在再灌流结束时反常地增加p38磷酸化。这些数据支持这样的观点，即O-GlcNAc可能作为一种内部应激反应发挥重要作用，而氨基葡萄糖诱导的心脏保护可能是通过p38MAPK途径介导的。
We have shown that, in the perfused heart, glucosamine improved functional recovery following ischemia and that this appeared to be mediated via an increase in O-linked N-acetylglucosamine (O-GlcNAc) levels on nucleocytoplasmic proteins. Several kinase pathways, specifically Akt and the mitogen-activated protein kinases (MAPKs) p38 and ERK1/2, which have been implicated in ischemic cardioprotection, have also been reported to be modified in response to increased O-GlcNAc levels. Therefore, the goals of this study were to determine the effect of ischemia on O-GlcNAc levels and to evaluate whether the cardioprotection resulting from glucosamine treatment could be attributed to changes in ERK1/2, Akt, and p38 phosphorylation. Isolated rat hearts were perfused with or without 5 mM glucosamine and were subjected to 5, 10, or 30 min of low-flow ischemia or 30 min of low-flow ischemia and 60 min of reperfusion. Glucosamine treatment attenuated ischemic contracture and improved functional recovery at the end of reperfusion. Glucosamine treatment increased flux through the hexosamine biosynthesis pathway and increased O-GlcNAc levels but had no effect on ATP levels. Glucosamine did not alter the response of either ERK1/2 or Akt to ischemia-reperfusion; however, it significantly attenuated the ischemia-induced increase in p38 phosphorylation and paradoxically increased p38 phosphorylation at the end of reperfusion. These data Support the notion that O-GlcNAc may play an important role as an internal stress response and that glucosamine-induced cardioprotection may be mediated via the p38 MAPK pathway.