Effects of Dexmedetomidine Postconditioning on Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Role of the PI3K/Akt-Dependent Signaling Pathway

Xiangyang Cheng, Jing Hu, Ya Wang, Hongwei Ye, Xiaohong Li, Qin Gao, Zhenghong Li, Xiangyang Cheng, Jing Hu, Ya Wang, Hongwei Ye, Xiaohong Li, Qin Gao, Zhenghong Li

Abstract

Objective: The present study was designed to determine whether dexmedetomidine (DEX) exerts cardioprotection against myocardial I/R injury in diabetic hearts and the mechanisms involved.

Methods: A total of 30 diabetic rats induced by high-glucose-fat diet and streptozotocin (STZ) were randomly assigned to five groups: diabetic sham-operated group (DM-S), diabetic I/R group (DM-I/R), diabetic DEX group (DM-D), diabetic DEX + Wort group (DM-DW), and diabetic Wort group (DM-W). Another 12 age-matched male normal SD rats were randomly divided into two groups: sham-operated group (S) and I/R group (I/R). All rats were subjected to 30 min myocardial ischemia followed by 120 min reperfusion except sham groups. Plasmas were collected to measure the malondialdehyde (MDA), creatine kinase isoenzymes (CK-MB), and lactate dehydrogenase (LDH) levels and superoxide dismutase (SOD) activity at the end of reperfusion. Pathologic changes in myocardial tissues were observed by H-E staining. The total and phosphorylated form of Akt and GSK-3β protein expressions were measured by western blot. The ratio of Bcl-2/Bax at mRNA level was detected by reverse transcription-polymerase chain reaction (RT-PCR).

Results: DEX significantly reduced plasma CK-MB, MDA concentration, and LDH level and increased SOD activity caused by I/R. The phosphorylation of Akt and GSK-3β was increased, Bcl-2 mRNA and the Bcl-2/Bax ratio was increased, and Bax mRNA was decreased in the DEX group as compared to the I/R group, while posttreatment with Wort attenuated the effects induced by DEX.

Conclusion: The results of this study suggest that DEX postconditioning may increase the phosphorylation of GSK-3β by activating the PI3K/Akt signaling pathway and may inhibit apoptosis and oxidative stress of the myocardium, thus exerting protective effects in diabetic rat hearts suffering from I/R injury.

Figures

Figure 1
Figure 1
The levels of CK-MB (a), LDH (b), SOD (c), and MDA (d) in the serum of rats from each group (mean ± SD, n = 6). ∗∗P < 0.01 compared with S; #P < 0.05; ##P < 0.01 compared with DM-S; ∧P < 0.05; ∧∧P < 0.01 compared with DM-I/R; &P < 0.05 compared with DM-D; S: sham-operated group; I/R: ischemia/reperfusion group; DM-S: diabetic sham-operated group; DM-I/R: diabetic ischemia/reperfusion group; DM-D: diabetic dexmedetomidine group; DM-DW: diabetic dexmedetomidine + wortmannin group; DM-W: diabetic wortmannin group.
Figure 2
Figure 2
Expression levels of p-Akt in heart tissue (mean ± SD, n = 4) ∗∗P < 0.01 compared with S; #P < 0.05 compared with DM-S.
Figure 3
Figure 3
Expression levels of p-Akt in heart tissue (mean ± SD, n = 4) ∗∗P < 0.01 compared with DM-I/R; ##P < 0.01 compared with DM-D.
Figure 4
Figure 4
Expression levels of p-GSK-3β (Ser9) in heart tissue (mean ± SD, n = 4). ∗P < 0.05 compared with S; ##P < 0.01 compared with DM-S.
Figure 5
Figure 5
Expression levels of p-GSK-3β (Ser9) in heart tissue (mean ± SD, n = 4). ∗P < 0.05 compared with DM-I/R; #P < 0.05 compared with DM-D.
Figure 6
Figure 6
The expressions of Bcl-2 and Bax mRNA in heart tissue (mean ± SD, n = 4). ∗P < 0.05; ∗∗P < 0.01 compared with S; #P < 0.05; ##P < 0.01 compared with DM-S; ∧P < 0.05; ∧∧P < 0.01 compared with DM-I/R; &P < 0.05 compared with DM-D.
Figure 7
Figure 7
The result of hematoxylin and eosin (H-E) staining cardiomyocytes (original magnification: ×400). (a) S group, (b) I/R group, (c) DM-S group, (d) DM-I/R group, (e) DM-D group, (f) DM-DW group, and (g) DM-W group.

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