Dexmedetomidine Ameliorates Cardiac Ischemia/Reperfusion Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT3 Pathway

Hong He; Peng Liu; Peng Li

doi:10.2147/DDDT.S428024

Dexmedetomidine Ameliorates Cardiac Ischemia/Reperfusion Injury by Enhancing Autophagy Through Activation of the AMPK/SIRT3 Pathway

Drug Des Devel Ther. 2023 Oct 25:17:3205-3218. doi: 10.2147/DDDT.S428024. eCollection 2023.

Authors

Hong He¹, Peng Liu², Peng Li¹

Affiliations

¹ Department of Anesthesiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610072 People's Republic of China.
² Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, 610044 People's Republic of China.

Abstract

Objective: Myocardial ischemia-reperfusion (I/R) injury is a detrimental disease, resulting in high morbidity and mortality globally. In this study, we aimed to investigate the role of Dex in mitigating cardiac I/R injury.

Methods: H9c2 cells were treated with Dex (1 μM) for 24 h followed by oxygen-glucose deprivation/re-oxygenation (OGD/R). ANP and BNP mRNA of H9c2 cells and the LDH release were measured. Apoptosis of H9c2 cells was analyzed by flow cytometry. Mitochondrial membrane potential and superoxide production were detected by JC-1 staining and MitoSOX^TM Red, respectively. Cell aerobic respiration was measured using Seahorse analysis. In vivo, mice were injected with Dex (25 μg/kg, i.p., once daily) for 5 days and then subjected to heart I/R. Heart function was analyzed by echocardiography. CK-MB and LDH were measured by Elisa. Infarct size was measured using TTC-Evans blue staining. Mitochondrial ultrastructure was observed using transmission electron microscopy. DHE staining, SOD activity, the content of MDA, and the content of GSH/GSSG of heart were measured to evaluate the oxidative stress. In addition, inflammatory cytokines were measured in vivo and in vitro. Furthermore, AMPK, SIRT3, and autophagy-related protein expression in the heart were detected by Western blot.

Results: Dex reduced the H9c2 cells injury exposed to OGD/R, accompanied by improved mitochondrial function and membrane potential. In vivo, Dex improved heart function, myocardial injury, and the mitochondria ultrastructure following I/R injury. Meanwhile, Dex inhibited myocardial oxidative stress and inflammation in the myocardial I/R. Furthermore, Compound C (an AMPK inhibitor) could inhibit Dex-induced autophagy in the I/R heart and the 3-MA (an autophagy inhibitor) could partially interfere with the effects of Dex on the protection of I/R heart.

Conclusion: Dex suppressed oxidative stress and inflammation by promoting autophagy through activating the AMPK/SIRT3 pathway, thus protecting the heart against the I/R injury.

Keywords: AMPK/SIRT3; autophagy; cardiac ischemia reperfusion; dexmedetomidine.

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Apoptosis
Autophagy
Dexmedetomidine* / pharmacology
Dexmedetomidine* / therapeutic use
Inflammation
Ischemia
Mice
Myocardial Ischemia* / metabolism
Myocardial Reperfusion Injury* / drug therapy
Myocardial Reperfusion Injury* / metabolism
Reperfusion Injury* / drug therapy
Signal Transduction
Sirtuin 3* / metabolism

Substances

AMP-Activated Protein Kinases
Dexmedetomidine
Sirtuin 3

Grants and funding

This work is supported by the Science and Technology Plan Project of Sichuan Province, China (2022YFS0439, 2022NSFSC1567, 2023YFS0137), Sichuan Provincial Cadre Health Research Fund (2022-221), and the National Natural Science Foundation of China (82170634).