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

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          Abstract

          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.

          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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          Most cited references 27

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          Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).

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            Autophagy in health and disease: a double-edged sword.

            Autophagy, the process by which cells recycle cytoplasm and dispose of excess or defective organelles, has entered the research spotlight largely owing to the discovery of the protein components that drive this process. Identifying the autophagy genes in yeast and finding orthologs in other organisms reveals the conservation of the mechanism of autophagy in eukaryotes and allows the use of molecular genetics and biology in different model systems to study this process. By mostly morphological studies, autophagy has been linked to disease processes. Whether autophagy protects from or causes disease is unclear. Here, we summarize current knowledge about the role of autophagy in disease and health.
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              Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003.

              To determine recent trends in rates of hospitalization, mortality, and hospital case fatality for severe sepsis in the United States. Trend analysis for the period from 1993 to 2003. U.S. community hospitals from the Nationwide Inpatient Sample that is a 20% stratified sample of all U.S. community hospitals. Subjects of any age with sepsis including severe sepsis who were hospitalized in the United States during the study period. None. Utilizing International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for septicemia and major organ dysfunction, we identified 8,403,766 patients with sepsis, including 2,857,476 patients with severe sepsis, who were hospitalized in the United States from 1993 to 2003. The percentage of severe sepsis cases among all sepsis cases increased continuously from 25.6% in 1993 to 43.8% in 2003 (p < .001). Age-adjusted rate of hospitalization for severe sepsis grew from 66.8 +/- 0.16 to 132.0 +/- 0.21 per 100,000 population (p < .001). Age-adjusted, population-based mortality rate within these years increased from 30.3 +/- 0.11 to 49.7 +/- 0.13 per 100,000 population (p < .001), whereas hospital case fatality rate fell from 45.8% +/- 0.17% to 37.8% +/- 0.10% (p < .001). During each study year, the rates of hospitalization, mortality, and case fatality increased with age. Hospitalization and mortality rates in males exceeded those in females, but case fatality rate was greater in females. From 1993 to 2003, age-adjusted rates for severe sepsis hospitalization and mortality increased annually by 8.2% (p < .001) and 5.6% (p < .001), respectively, whereas case fatality rate decreased by 1.4% (p < .001). The rate of severe sepsis hospitalization almost doubled during the 11-yr period studied and is considerably greater than has been previously predicted. Mortality from severe sepsis also increased significantly. However, case fatality rates decreased during the same study period.
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                Author and article information

                Journal
                Chin Med J (Engl)
                Chin. Med. J
                CMJ
                Chinese Medical Journal
                Medknow Publications & Media Pvt Ltd (India )
                0366-6999
                20 May 2018
                : 131
                : 10
                : 1185-1190
                Affiliations
                Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China
                Author notes
                Address for correspondence: 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 E-Mail: dwliu98@ 123456163.com
                Article
                CMJ-131-1185
                10.4103/0366-6999.231522
                5956769
                29722337
                Copyright: © 2018 Chinese Medical Journal

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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