Journal Article

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

Cui, Na, Liu, Da-Wei, Han, Wen, Long, Yun, Su, Long-Xiang, Wang, Hao

2018

Overview

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.

• Publisher: Wolters Kluwer India Pvt. Ltd,Medknow Publications and Media Pvt. Ltd,Lippincott Williams & Wilkins Ovid Technologies,Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science,Beijing 100730, China,Medknow Publications & Media Pvt Ltd,Wolters Kluwer
• Subject: Animals / Autophagy / Autophagy - physiology / Autophagy; Cecal Ligation and Puncture; Mammalian Target of Rapamycin; Myocardial Dysfunction; Sepsis / Cecum - injuries / Critical care / Dosage and administration / Drug therapy / Echocardiography / Ejection fraction / Genetic aspects / Heart / Heart attack / Immunohistochemistry / Ischemia / Kinases / Ligation / Male / Medicine / Microscopy, Electron, Transmission / Myocardium - metabolism / Original / Phosphorylation / Proteins / Rapamycin / Rats / Rats, Wistar / Risk factors / Rodents / Science / Sepsis / Sepsis - metabolism / Software / TOR Serine-Threonine Kinases - metabolism / Transmission electron microscopy