Inhibition of IκB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury
Inhibition of IκB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury
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DOI：
10.1016/j.cardiores.2004.03.002
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发表时间：
2004-07-01
影响因子：
10.8
通讯作者：
Isobe, M
中科院分区：
文献类型：
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作者：
Onai, Y;Suzuki, J;Isobe, M
目的：再灌注损伤与炎症细胞的活化、细胞毒性细胞因子的表达等炎症反应密切相关。我们研究IkappaB磷酸化阻断剂对大鼠心肌缺血/再灌注损伤模型的影响。方法和结果：IMD-0354抑制培养的心肌细胞中由特纳坏死因子- α (tnf - α)诱导的ikappabα磷酸化和核因子- κ B （nf - κ B）核易位。IMD-0354可显著降低tnf - α诱导的心肌细胞白细胞介素- β和单核细胞趋化蛋白-1的产生。Sprague-Dawley大鼠进行短暂左冠状动脉闭塞（30min）和再灌注（24h）。IMD-0354（1、5、10 mg/kg）于再灌注开始前5 min腹腔注射。IMD-0354治疗可显著降低梗死面积/危险面积比（对照，47.0 +/- 3.4%;IMD-0354 10 mg/kg, 19.4 +/- 4.0%, P < 0.01），并保持小段缩短比（对照，25.0 +/- 1.5%;IMD-0354 10 mg/kg）。42.3 +/- 1.7%；P < 0.01)。组织学分析显示，多形核中性粒细胞在危险区域的积累明显减少。结论：IkappaBalpha磷酸化阻断剂抑制NF-kappaB核易位是减轻缺血再灌注损伤的有效途径。IMD-0354的心脏保护作用不仅包括减少心肌中有害中性粒细胞的积累，还包括抑制心肌细胞有害细胞因子和趋化因子的产生。(C) 2004欧洲心脏病学会。Elsevier B.V.版权所有。
objective: Reperfusion injury is related closely to inflammatory reactions such as activation of inflammatory cells and expression of cytotoxic cytokines. We investigated the efficacy of IkappaB phosphorylation blockade in a rat myocardial ischemia/reperfusion injury model. Methods and results: IMD-0354 inhibited phosphorylation of IkappaBalpha and nuclear translocation of nuclear factor-kappa B (NF-kappaB) induced by turner necrosis factor-alpha (TNF-alpha) in cultured cardiomyocytes. TNF-alpha-induced production of interleukin-lbeta and monocyte chemoattractant protein-1 from Cultured cardiomyocytes was reduced significantly by IMD-0354. Transient left coronary artery occlusion (30 min) and reperfusion (24 h) were carried out in Sprague-Dawley rats. IMD-0354 (1, 5, 10 mg/kg) was injected intraperitoneally 5 min before the start of reperfusion. Treatment with IMD-0354 resulted in a significant dose-dependent reduction of the infarction area/area at risk ratio (vehicle, 47.0 +/- 3.4%; 10 mg/kg of IMD-0354, 19.4 +/- 4.0%; P < 0.01) and the preservation of fractional shortening ratio (vehicle, 25.0 +/- 1.5%; 10 mg/kg of IMD-0354. 42.3 +/- 1.7%; P < 0.01). Histological analysis showed that accumulation of polymorphonuclear neutrophils in the area at risk was decreased significantly. Conclusions: Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.