Inhibition of the mTOR Pathway Exerts Cardioprotective Effects Partly through Autophagy in CLP Rats.
Inhibition of the mTOR Pathway Exerts Cardioprotective Effects Partly through Autophagy in CLP Rats.
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DOI：
10.1155/2018/4798209
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发表时间：
2018
影响因子：
4.6
通讯作者：
Liu D
中科院分区：
文献类型：
--
作者：
Han W;Wang H;Su L;Long Y;Cui N;Liu D
脓毒症引起的心肌功能障碍是一个严重的临床问题。最近的研究表明，自噬和心肌能量消耗在脓毒症期间的心肌功能障碍中起主要作用，雷帕霉素（mTOR）作为能量状态和自噬介体的主传感器的机制靶点;然而，很少有数据描述其在心脏脓毒症期间的作用。 采用盲肠结扎穿孔术（CLP）和假手术（SHAM）方法建立大鼠盲肠结扎穿孔模型。治疗结束后，采用H&E染色观察心肌病理变化，超声心动图观察心功能变化，免疫组化染色观察微管相关蛋白轻链3（LC-3）Ⅱ型和缺氧诱导因子1α（HIF-1a）的分布，透射电镜观察自噬空泡。此外，mTOR信号通路和LC 3 II，p62，和HIF-1a的表达通过蛋白质印迹法测定。 雷帕霉素可减轻心肌组织病理损伤，减轻心功能不全（左室射血分数（LVEF），P < 0.05;左室短轴缩短率（FS），P < 0.05），降低HIF-1a表达（P < 0.05）。预期雷帕霉素降低了假手术大鼠（p < 0.0001）和CLP大鼠（p < 0.01）中mTOR通路的活性。有趣的是，我们还发现与假手术大鼠相比，CLP大鼠中的mTOR通路受到抑制;在CLP攻击后，mTOR（p < 0.001）和pS 6 K1（p < 0.01）的磷酸化均受到显著抑制。CLP组自噬过程明显增强，LC 3 II/LC 3 I比值增加（p < 0.05），p62表达明显降低（p < 0.001），自噬空泡增多，雷帕霉素可进一步增强自噬过程（LC 3 II/LC 3 I，p < 0.05; P62，p < 0.05）。 抑制mTOR通路对CLP诱导的脓毒症期间的心肌功能障碍具有心脏保护作用，这部分是通过自噬介导的。
Sepsis-induced myocardial dysfunction is a severe clinical problem. Recent studies have indicated that autophagy and myocardial energy depletion play a major role in myocardial dysfunction during sepsis, a mechanistic target of rapamycin (mTOR) as a master sensor of energy status and autophagy mediator; however, there are little data describing its role during sepsis in the heart. Cecal ligation and puncture (CLP) or sham operation (SHAM) was performed in rats. After treatment, pathological changes were determined by H&E staining, cardiac functions by echocardiography, the distribution of microtubule-associated protein light chain 3 (LC-3) type II and hypoxia-inducible factor 1α (HIF-1a) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, the mTOR signaling pathway and LC3II, p62, and HIF-1a expression were measured by western blotting. Rapamycin alleviated the pathological damage of myocardial tissue, attenuated cardiac dysfunction (left ventricular ejection fraction (LVEF), p < 0.05; fractional shortening (FS), p < 0.05), and reduced HIF-1a expression (p < 0.05). Expectedly, rapamycin decreased the activity of the mTOR pathway in both sham-operated rats (p < 0.0001) and CLP rats (p < 0.01). Interestingly, we also found inhibition of the mTOR pathway in CLP rats compared with sham-operated rats; phosphorylation of both mTOR (p < 0.001) and pS6K1 (p < 0.01) was significantly suppressed following CLP challenge. Furthermore, autophagic processes were elevated by CLP; the ratio of LC3II/LC3I (p < 0.05) was increased while p62 expression (p < 0.001) was decreased significantly; there were also more autophagic vacuoles in CLP rats; and rapamycin could further elevate the autophagic processes compared with CLP rats (LC3II/LC3I, p < 0.05; P62, p < 0.05). Inhibition of the mTOR pathway has cardioprotective effects on myocardial dysfunction during sepsis induced by CLP, which is partly mediated through autophagy.
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影响因子：
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