Effects of dexmedetomidine on myocardial ischemia-reperfusion injury through PI3K-Akt-mTOR signaling pathway
Authors: D-H Liu
H Jiang
J Zhang
G-N Wang
Journal: European review for medical and pharmacological sciences (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Dexmedetomidine; Myocardial ischemia-reperfusion injury; Molecular mechanism; Rats; Rapamycin
Affiliations: Department of Anesthesiology, Cancer Hospital of Harbin Medical University, Harbin, China. .

Abstract:  Objective: To explore the role of dexmedetomidine (DEX) in myocardial ischemia-reperfusion (I/R) injury model and investigate its specific molecular mechanism. Materials and methods: The I/R rat model was established by ligating the anterior descending coronary artery for 30 min and reperfusion for 120 min. In this experiment, all rats were divided into sham operation (SH) group, I/R group, DEX group and I/R + rapamycin (RAP) group. After 120 min of I/R treatment, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximal rates of rise and fall of left ventricular pressure (±dp/dtmax) and ischemic area were detected. Serum samples of rats in each group were collected. The levels of catalase (CAT), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), superoxide dismutase (SOD), creatine kinase (CK), CK-muscle/brain (CK-MB), tumor necrosis factor (TNF) and interleukin-6 (IL-6) were detected using enzyme-linked immunosorbent assay (ELISA). The apoptosis of myocardium in each group was detected according to the instructions of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expressions of mammalian target of rapamycin (mTOR), phosphorylated-mTOR (p-mTOR), protein kinase B (Akt) and p-Akt in myocardial tissues were detected via Western blotting. Moreover, the messenger ribonucleic acid (mRNA) expression level of mTOR in each group was detected using reverse transcription-polymerase chain reaction (RT-PCR). Results: Compared with SH group, LVSP and ±dp/dtmax in I/R group were significantly decreased, whereas LVEDP was remarkably increased in I/R group (p&lt;0.01). After DEX administration, LVSP and ±dp/dtmax were remarkably increased, while LVEDP and infarction area were markedly decreased (p&lt;0.01). After treatment with mTOR inhibitor rapamycin (RAP), LVSP and ±dp/dtmax were evidently decreased, while LVEDP and infarction area were increased when compared with those of DEX group (p&lt;0.01). Compared with SH group, the levels of CK, CK-MB, TNF-α and IL-6 in I/R group were significantly increased. However, the levels of these molecules were significantly decreased after DEX treatment in I/R rats. After the combination of DEX and RAP, the expression levels of these indexes were significantly increased. No significant differences were found between DEX + RAP group and model group, and between I/R + RAP group and model group. MDA level in I/R group was significantly higher than that of SH group, while the levels of SOD, CAT and GSH-PX were notably lower (p&lt;0.01). Compared with I/R group, the level of MDA in DEX group was significantly reduced, but the levels of SOD, CAT and GSH-PX were markedly increased (p&lt;0.05, p&lt;0.01). Meanwhile, compared with DEX group, MDA level in I/R group was significantly increased. However, the levels of SOD, CAT and GSH-PX were remarkably decreased after the application of combined DEX and mTOR inhibitor (p&lt;0.01). After the addition of RAP, no significant changes were found in each index compared with I/R group. DEX could alleviate myocardial cell apoptosis caused by I/R treatment (p&lt;0.01). The levels of p-mTOR and p-Akt in I/R group were significantly increased when compared with those of SH group. However, the levels of these indexes in DEX group were evidently higher than those of I/R group after DEX administration based on myocardial I/R model (p&lt;0.01). After combination of DEX and RAP, the latter canceled the effect of the former on enhancing the expression of p-mTOR and the phosphorylation level of mTOR. Furthermore, there was no significant change in mTOR and its mRNA expression in each group. Conclusions: DEX can play a protective role in myocardial I/R rats, improve the cardiac function of I/R rats, eliminate oxygen free radicals, relieve oxidative stress injury, inhibit inflammatory responses and reduce the release of CK and other substances. The myocardial protection effects of DEX are mainly achieved through the phosphatidylin-ositol-3-kinase (PI3K)-Akt-mTOR pathway. 

Retracted: No

PubPeer comments:
 Could the authors comment on what appear to be some repeated features? ![file] , 
 Fig 9. A and C are the same apart from a 180-deg flip. B is just blank. ![file] , 
 #1 I am not an expert but I would have expected **some** variation in the fine-level noise and in the regularity of the horizontal axis. ![file] ,