Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents.
Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents.
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DOI：
10.1155/2015/129612
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发表时间：
2015
影响因子：
--
通讯作者：
Gross ER
中科院分区：
文献类型：
--
作者：
Small BA;Lu Y;Hsu AK;Gross GJ;Gross ER
阿片类药物可减轻人类心肌缺血再灌注造成的损伤。在实验模型中，该机制涉及 GSK3β 抑制。 HSP90 调节线粒体蛋白输入，抑制 GSK3β 会增加 HSP90 线粒体含量。因此，我们确定吗啡诱导的心脏保护作用是否由 HSP90 介导，以及保护作用是否是 GSK3β 抑制的下游。 8-10 周龄的雄性 Sprague-Dawley 大鼠接受体内心肌缺血再灌注损伤方案，其中包括 30 分钟缺血，然后 2 小时再灌注。持续监测血流动力学并确定心肌梗塞面积。大鼠在缺血前 10 分钟接受吗啡 (0.3mg/kg)、GSK3β 抑制剂 SB216763 (0.6mg/kg) 或生理盐水。一些大鼠单独接受选择性HSP90抑制剂、根赤考（0.3mg/kg）或脱氧精胍菌素（DSG，0.6mg/kg）或在吗啡或SB216763前5分钟接受。与对照组相比，吗啡减少了心肌梗塞面积（42 ± 2% 与 60 ± 1%）。这种保护作用通过先前的根底考或 DSG 治疗而被消除（59 ± 1%、56 ± 2%）。 GSK3β 抑制还减少了心肌梗塞面积 (41 ± 2%)，而根赤考或 DSG 抑制 HSP90 部分抑制了 SB216763 诱导的梗塞面积减少 (分别为 54 ± 3%、47 ± 1%)。这些数据表明阿片类药物诱导的心脏保护作用是由 HSP90 介导的。 HSP90 提供的部分保护位于 GSK3β 下游，可能通过 HSP-TOM 线粒体输入途径。
Opioids reduce injury from myocardial ischemia-reperfusion in humans. In experimental models, this mechanism involves GSK3β inhibition. HSP90 regulates mitochondrial protein import, with GSK3β inhibition increasing HSP90 mitochondrial content. Therefore, we determined whether morphine-induced cardioprotection is mediated by HSP90 and if the protective effect is downstream of GSK3β inhibition. Male Sprague-Dawley rats, aged 8–10 weeks, were subjected to an in vivo myocardial ischemia-reperfusion injury protocol involving 30 minutes of ischemia followed by 2 hours of reperfusion. Hemodynamics were continually monitored and myocardial infarct size determined. Rats received morphine (0.3 mg/kg), the GSK3β inhibitor, SB216763 (0.6 mg/kg), or saline, 10 minutes prior to ischemia. Some rats received selective HSP90 inhibitors, radicicol (0.3 mg/kg), or deoxyspergualin (DSG, 0.6 mg/kg) alone or 5 minutes prior to morphine or SB216763. Morphine reduced myocardial infarct size when compared to control (42 ± 2% versus 60 ± 1%). This protection was abolished by prior treatment of radicicol or DSG (59 ± 1%, 56 ± 2%). GSK3β inhibition also reduced myocardial infarct size (41 ± 2%) with HSP90 inhibition by radicicol or DSG partially inhibiting SB216763-induced infarct size reduction (54 ± 3%, 47 ± 1%, resp.). These data suggest that opioid-induced cardioprotection is mediated by HSP90. Part of this protection afforded by HSP90 is downstream of GSK3β, potentially via the HSP-TOM mitochondrial import pathway.