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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 10  |  Page : 1185-1190

Accelerated Autophagy of Cecal Ligation and Puncture-Induced Myocardial Dysfunction and Its Correlation with Mammalian Target of Rapamycin Pathway in Rats


Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China

Correspondence Address:
Dr. Da-Wei Liu
Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.231522

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Background: Recent studies have indicated that autophagy is involved in sepsis-induced myocardial dysfunction. This study aimed to investigate the change of autophagy in cecal ligation and puncture (CLP)-induced myocardium dysfunction and its relationship with mammalian target of rapamycin (mTOR) pathway. Methods: Totally, 12 rats were randomly divided into CLP group or sham-operated (SHAM) group. Cardiac tissues were harvested 18 h after CLP or sham operation. Pathology was detected by hematoxylin and eosin staining, cardiac functions by echocardiography, distribution of microtubule-associated protein light chain 3 type II (LC3II) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, phosphorylation of mTOR (p-mTOR), phosphorylation of S6 kinase-1 (PS6K1), and LC3II and p62 expression were measured by western blotting. Pearson's correlation coefficient was used to analyze the correlation of two parameters. Results: The results by pathology and echocardiography revealed that there was obvious myocardial injury in CLP rats (left ventricle ejection fraction: SHAM 0.76 ± 0.06 vs. CLP 0.59 ± 0.11, P < 0.01; fractional shortening: SHAM 0.51 ± 0.09 vs. CLP 0.37 ± 0.06, P < 0.05). We also found that the autophagy process was elevated by CLP, the ratio of LC3II/LC3I was increased (P < 0.05) while the expression of p62 was decreased (P < 0.05) in the CLP rats, and there were also more autophagosomes and autolysosomes in the CLP rats. Furthermore, the mTOR pathway in CLP myocardium was inhibited when compared with the sham-operated rats; p-mTOR (P < 0.01) and PS6K1 (P < 0.05) were both significantly suppressed following CLP challenge. Interestingly, we found that the mTOR pathway was closely correlated with the autophagy processes. In our study, while p-mTOR in the myocardium was significantly correlated with p62 (r = 0.66, P = 0.02), PS6K1 was significantly positively correlated with p62 (r = 0.70, P = 0.01) and negatively correlated with LC3II (r = −0.71, P = 0.01). Conclusions: The autophagy process in the myocardium was accelerated in CLP rats, which was closely correlated with the inhibition of the mTOR pathway.

 

 Abstract in Chinese

CLP诱导的大鼠心肌功能障碍中的加速自噬与mTOR信号通路的关系


摘要

背景:最近的研究表明,自噬参与脓毒症引起的心肌功能障碍。本研究旨在探讨在盲肠结扎穿孔(CLP)诱导的心肌功能障碍中自噬的变化,以及与哺乳动物雷帕霉素靶蛋白(mTOR)信号通路的关系。

方法:12只大鼠随机分为CLP组和假手术组。在CLP或假手术后18小时收集心脏组织。苏木精和伊红染色(H&E)检测病理,超声心动图检查心脏功能,免疫组织化学染色检测II型微管相关蛋白轻链3(LC-3)的分布,II型,透射电子显微镜检测自噬泡。此外,应用蛋白质印迹法检测磷酸化mTOR(p-mTOR),磷酸化核糖体S6蛋白激酶(ps6k1),LC3II和p62的表达。皮尔森相关系数用于分析两个参数之间的相关性。

结果:病理和超声心动图显示,CLP大鼠心肌明显损伤。我们还发现CLP大鼠中自噬进程的升高,LC3II/LC3I比值升高(P<0.05),p62的表达明显降低(P<0.05),CLP大鼠有更多的自噬体和自噬溶酶体。此外,在CLP组中,与假手术组相比,心肌mTOR信号通路被抑制,CLP后p-mTOR(P<0.01)和ps6k1(P<0.05)均显著下降。有趣的是,我们发现mTOR信号通路与细胞自噬过程密切相关。在我们的研究中发现,心肌组织中p-mTOR和P62显著相关(r = 0.66,P = 0.02),ps6k1与 p62呈显著正相关(r = 0.70, P = 0.01),与LC3II负相关(r = -0.71,P = 0.01)。

结论:CLP大鼠心肌自噬的过程加快与mTOR信号通路的抑制密切相关。



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