Deferoxamine induces prolonged cardiac preconditioning via accumulation of oxygen radicals
Deferoxamine induces prolonged cardiac preconditioning via accumulation of oxygen radicals
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DOI：
10.1016/j.freeradbiomed.2004.10.015
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发表时间：
2005-01-01
影响因子：
7.4
通讯作者：
Dominiak, P
中科院分区：
文献类型：
--
作者：
Dendorfer, A;Heidbreder, M;Dominiak, P
通过去铁胺（DFO）的铁螯合作用阻断芬顿反应，但也抑制脯氨酰羟化酶，从而激活某些缺氧诱导的转录因子（HIF），其触发细胞对缺氧的适应。由于这两种机制都可以减轻缺血和再灌注时的组织损伤，我们试图区分它们对DFO诱导的心脏保护作用的贡献。在麻醉Wistar大鼠中诱导心肌缺血和再灌注。冠状动脉大小与缺血面积有关。实时荧光定量PCR检测心肌mRNA表达。用氧化还原敏感染料CM-H（2）DCFDA探测心肌组织切片中的自由基反应性。在梗死前2小时至3天单次ip应用DFO（200 mg/kg）可将梗死面积从55 +/-7%降至22 - 26%。当在DFO前30分钟给予自由基清除剂N-（2-巯基丙酰基）甘氨酸和蛋白激酶C抑制剂白屈菜红碱时，保护作用被消除，而随后的应用则无效。DFO并没有改变各种HIE靶基因的表达，而HIF非依赖性基因，醛糖还原酶和葡萄糖转运蛋白-4的mRNA，在梗死心肌DFO治疗后2天增加。体外实验表明，DFO可增强超氧阴离子的活性。DFO通过引起氧自由基的积累和蛋白激酶C的激活而触发急性和长期的心肌预适应。(C)2004爱思唯尔公司All rights reserved.
Iron chelation by deferoxamine (DFO) blocks the Fenton reaction, but also inhibits prolyl hydroxylases and thereby activates certain hypoxia-inducible transcription factors (HIFs) that trigger cellular adaptation to hypoxia. Because both mechanisms may alleviate tissue damage in ischemia and reperfusion, we tried to differentiate their contribution to DFO-induced cardioprotection. Myocardial ischemia and reperfusion were induced in anesthetized Wistar rats. Infarct size was related to the ischemic area. Myocardial mRNA expression was determined by real-time PCR. Radical reactivity was probed in myocardial tissue slices with the redox-sensitive dye CM-H(2)DCFDA. Single ip applications of DFO (200 mg/kg) administered 2 h to 3 days before infarction reduced infarct size from 55 +/- 7% to 22-26%. Protection was abolished by the radical scavenger N-(2-mercaptopropionyl)glycine and the protein kinase C inhibitor chelerythrine when either was given 30 mm before DFO, whereas subsequent application was ineffective. DFO did not alter the expression of various HIE target genes, whereas mRNAs of HIF-independent genes, aldose reductase and glucose transporter-4, were increased in infarcted myocardium 2 days after DFO treatment. Enhancement of superoxide activity by DFO could be demonstrated in vitro. Acute and prolonged myocardial preconditioning is triggered by DFO in response to accumulation of oxygen radicals and activation of protein kinase C. (C) 2004 Elsevier Inc. All rights reserved.