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

摘要

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 ofmicrotubule-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.l l,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 CLE 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 PS6K 1 (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 LC31I (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.