Increased hexosamine biosynthesis and protein O-GlcNAc levels associated with myocardial protection against calcium paradox and ischemia
Increased hexosamine biosynthesis and protein O-GlcNAc levels associated with myocardial protection against calcium paradox and ischemia
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DOI：
10.1016/j.yjmcc.2005.11.003
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发表时间：
2006-02-01
影响因子：
5
通讯作者：
Marchase, RB
中科院分区：
文献类型：
--
作者：
Liu, J;Pang, Y;Marchase, RB
己糖胺生物合成途径（HBP）通量的增加和蛋白o -连接- n -乙酰氨基葡萄糖（O-GlcNAc）水平的升高减少了钙流入离体心肌细胞。O-GlcNAc水平的增加也增加了细胞对压力的耐受性。因此，本研究的目的是验证完整心脏中HBP通量和蛋白O-GlcNAc水平的增加是否会增加对钙悖论和缺血引起的组织损伤的耐受性。我们采用了两种已被证明可以增加完整心脏中HBP通量的策略，即短暂的链脲佐菌素诱导的糖尿病和用葡萄糖胺对离体灌注心脏进行急性预处理。离体灌注大鼠心脏暴露于钙悖论或缺血再灌注。在钙悖论后，糖尿病和葡萄糖胺显著改善了离体灌注大鼠心脏的恢复，左心室发展压力（LVDP）恢复到基线的80%，而对照组为0% (P < 0.05)，乳酸脱氢酶释放减少了大约五倍（P < 0.05）。在糖尿病组中。抑制HBP的azazerine恢复了对钙悖论的敏感性。葡萄糖胺治疗也改善了缺血/再灌注后的功能恢复（LVDP: 47 +/- 9% vs 95 +/- 4%, P < 0.05），这与O-GlcNAc水平增加三倍相关（P < 0.05）。O-GlcNAc转移酶抑制剂四氧嘧啶阻断了氨基葡萄糖的保护作用和O-GlcNAc的增加。这些数据表明，用葡萄糖氨酸激活FIBP可能是一种诱导心脏保护的新策略，这似乎是由O-GlcNAc蛋白水平的增加介导的。(c) 2005 Elsevier Ltd版权所有。
Increased hexosamine biosynthesis pathway (HBP) flux and elevated levels of protein O-linked-N-acetylglucosamine (O-GlcNAc) decrease calcium influx into isolated cardiomyocytes. Increased O-GlcNAc levels also increase tolerance of cells to stress. Therefore, the goal of this study was to test the hypothesis that increasing HBP flux and protein O-GlcNAc levels in the intact heart will increase the tolerance to tissue injury resulting from the calcium paradox and ischemia. We used two strategies that have been shown to increase HBP flux in the intact heart, namely a brief period of streptozotocin-induced diabetes and acute pretreatment of the isolated perfused heart with glucosamine. Isolated perfused rat hearts were exposed to the calcium paradox or to ischemia and reperfusion. Both diabetes and glucosamine significantly improved recovery in the isolated perfused rat heart following the calcium paradox with left ventricular developed pressure (LVDP) returning to similar to 80% of baseline compared to 0% in controls (P < 0.05), and lactate dehydrogenase release being reduced by approximately fivefold (P < 0.05). In the diabetic group. azaserine, which inhibits the HBP, restored the sensitivity to the calcium paradox. Glucosamine treatment also improved functional recovery following ischemia/reperfusion (LVDP: 47 +/- 9% vs. 95 +/- 4%, P < 0.05) and this was associated with a threefold increase in O-GlcNAc levels (P < 0.05). Alloxan, ail inhibitor of O-GlcNAc-transferase, blocked both the protection Seen With glucosamine and the increase in O-GlcNAc. These data demonstrate that activation of the FIBP with glucosarnine may be a novel strategy for inducing cardioprotection, and that this appears to be mediated by ail increase in protein O-GlcNAc levels. (c) 2005 Elsevier Ltd. All rights reserved.