Dexmedetomidine Protects Human Cardiomyocytes Against Ischemia-Reperfusion Injury Through α2-Adrenergic Receptor/AMPK-Dependent Autophagy

Overview

Journal Front Pharmacol

Date 2021 Jun 7

PMID 34093174

Citations 12

Authors

Yingying Xiao

Junpeng Li

Lisheng Qiu

Chuan Jiang

Yanhui Huang

Jinfen Liu

Qi Sun

Haifa Hong

Lincai Ye

Affiliations

Soon will be listed here.

Abstract

Ischemia-reperfusion injury (I/R) strongly affects the prognosis of children with complicated congenital heart diseases (CHDs) who undergo long-term cardiac surgical processes. Recently, the α2-adrenergic receptor agonist (Dex) has been reported to protect cardiomyocytes (CMs) from I/R in cellular models and adult rodent models. However, whether and how Dex may protect human CMs in young children remains largely unknown. Human ventricular tissue from tetralogy of Fallot (TOF) patients and CMs derived from human-induced pluripotent stem cells (iPSC-CMs) were used to assess whether and how Dex protects human CMs from I/R. The results showed that when pretreated with Dex, the apoptosis marker-TUNEL and cleaved caspase 3 in the ventricular tissue were significantly reduced. In addition, the autophagy marker LC3II was significantly increased compared with that of the control group. When exposed to the hypoxia/reoxygenation process, iPSC-CMs pretreated with Dex also showed reduced TUNEL and cleaved caspase 3 and increased LC3II. When the autophagy inhibitor (3-methyladenine, 3-MA) was applied to the iPSC-CMs, the protective effect of Dex on the CMs was largely blocked. In addition, when the fusion of autophagosomes with lysosomes was blocked by Bafilomycin A1, the degradation of p62 induced by Dex during the autophagy process was suspended. Moreover, when pretreated with Dex, both the human ventricle and the iPSC-CMs expressed more AMP-activated protein kinase (AMPK) and phospho AMPK (pAMPK) during the I/R process. After AMPK knockout or the use of an α2-adrenergic receptor antagonist-yohimbine, the protection of Dex and its enhancement of autophagy were inhibited. Dex protects young human CMs from I/R injury, and α2-adrenergic receptor/AMPK-dependent autophagy plays an important role during this process. Dex may have a therapeutic effect for children with CHD who undergo long-term cardiac surgical processes.

Citing Articles

Cardioprotective effects of the electrolyte solution sterofundin and the possible underlying mechanisms.

Chen M, Xiao Y, Zheng J, Zhao P, Cheng L, Jiang C Front Pharmacol. 2025; 15():1449831.

PMID: 39830345 PMC: 11738938. DOI: 10.3389/fphar.2024.1449831.

Dexmedetomidine regulates the anti-oxidation and autophagy of adipose-derived stromal cells under HO-induced oxidative stress through Nrf2/p62 pathway and improves the retention rate of autologous fat transplantation.

Li Z, Wei Q, Li Y, Yang F, Ke C, Li T Front Pharmacol. 2024; 15:1453938.

PMID: 39654626 PMC: 11625574. DOI: 10.3389/fphar.2024.1453938.

Dexmedetomidine Attenuated Neuron Death, Cognitive Decline, and Anxiety-Like Behavior by Inhibiting CXCL2 in CA1 Region of AD Mice.

Ma K, An C, Li M, Zhang Y, Ren M, Wei Y Drug Des Devel Ther. 2024; 18:5351-5365.

PMID: 39605963 PMC: 11600949. DOI: 10.2147/DDDT.S489860.

The Current State of Realistic Heart Models for Disease Modelling and Cardiotoxicity.

Kistamas K, Lamberto F, Vaiciuleviciute R, Leal F, Muenthaisong S, Marte L Int J Mol Sci. 2024; 25(17).

PMID: 39273136 PMC: 11394806. DOI: 10.3390/ijms25179186.

Insight into Cardioprotective Effects and Mechanisms of Dexmedetomidine.

Jiang L, Xiong W, Yang Y, Qian J Cardiovasc Drugs Ther. 2024; 38(6):1139-1159.

PMID: 38869744 DOI: 10.1007/s10557-024-07579-9.

References

Wang J, Chen X, Shen D, Ge D, Chen J, Pei J . A long noncoding RNA NR_045363 controls cardiomyocyte proliferation and cardiac repair. J Mol Cell Cardiol. 2018; 127:105-114. DOI: 10.1016/j.yjmcc.2018.12.005. View

Zlatanova I, Pinto C, Bonnin P, Mathieu J, Bakker W, Vilar J . Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury. Circulation. 2018; 139(12):1530-1547. DOI: 10.1161/CIRCULATIONAHA.118.034545. View

Li Y, Liang P, Jiang B, Tang Y, Liu X, Liu M . CARD9 promotes autophagy in cardiomyocytes in myocardial ischemia/reperfusion injury via interacting with Rubicon directly. Basic Res Cardiol. 2020; 115(3):29. DOI: 10.1007/s00395-020-0790-6. View

Bezzerides V, Caballero A, Wang S, Ai Y, Hylind R, Lu F . Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca/Calmodulin-Dependent Kinase II. Circulation. 2019; 140(5):405-419. PMC: 7274838. DOI: 10.1161/CIRCULATIONAHA.118.038514. View

Harris V . Protein detection by Simple Western™ analysis. Methods Mol Biol. 2015; 1312:465-8. DOI: 10.1007/978-1-4939-2694-7_47. View

Mookherjee D, Das S, Mukherjee R, Bera M, Jana S, Chakrabarti S . RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1 -a dual organellar turnover mechanism. Autophagy. 2020; 17(7):1729-1752. PMC: 8354597. DOI: 10.1080/15548627.2020.1783118. View

Davidson S, Adameova A, Barile L, Cabrera-Fuentes H, Lazou A, Pagliaro P . Mitochondrial and mitochondrial-independent pathways of myocardial cell death during ischaemia and reperfusion injury. J Cell Mol Med. 2020; 24(7):3795-3806. PMC: 7171390. DOI: 10.1111/jcmm.15127. View

Zhao L, Chen L, Yang T, Wang T, Zhang S, Chen L . Birth prevalence of congenital heart disease in China, 1980-2019: a systematic review and meta-analysis of 617 studies. Eur J Epidemiol. 2020; 35(7):631-642. PMC: 7387380. DOI: 10.1007/s10654-020-00653-0. View

Li W, Kennedy D, Shao Z, Wang X, Klaassen Kamdar A, Weber M . Paraoxonase 2 prevents the development of heart failure. Free Radic Biol Med. 2018; 121:117-126. PMC: 5971153. DOI: 10.1016/j.freeradbiomed.2018.04.583. View

10.

Zhou H, Zhou D, Lu J, Wu C, Zhu Z . Effects of Pre-Cardiopulmonary Bypass Administration of Dexmedetomidine on Cardiac Injuries and the Inflammatory Response in Valve Replacement Surgery With a Sevoflurane Postconditioning Protocol: A Pilot Study. J Cardiovasc Pharmacol. 2019; 74(2):91-97. PMC: 6688713. DOI: 10.1097/FJC.0000000000000698. View

11.

Ponnusamy M, Liu F, Zhang Y, Li R, Zhai M, Liu F . Long Noncoding RNA CPR (Cardiomyocyte Proliferation Regulator) Regulates Cardiomyocyte Proliferation and Cardiac Repair. Circulation. 2019; 139(23):2668-2684. DOI: 10.1161/CIRCULATIONAHA.118.035832. View

12.

Bailey C . Dexmedetomidine in children - when should we be using it?. Anaesthesia. 2020; 76(3):309-311. DOI: 10.1111/anae.15169. View

13.

Wiswell D, Neupane D, Chen M, Bowman E, Linn D, Sawant A . A capillary electrophoresis based approach for the identification of anti-drug antibodies against camelid VHH biologics (Nanobodies®). J Pharmacol Toxicol Methods. 2020; 103:106872. DOI: 10.1016/j.vascn.2020.106872. View

14.

Peng K, Chen W, Xia F, Liu H, Meng X, Zhang J . Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1α signalling. J Cell Mol Med. 2019; 24(1):850-861. PMC: 6933328. DOI: 10.1111/jcmm.14795. View

15.

Wang D, Chen T, Liu F . Betulinic acid alleviates myocardial hypoxia/reoxygenation injury via inducing Nrf2/HO-1 and inhibiting p38 and JNK pathways. Eur J Pharmacol. 2018; 838:53-59. DOI: 10.1016/j.ejphar.2018.08.024. View

16.

Hascoet S, Boet A, Roussin R, Guihaire J, Savale L, Mercier O . Pumpless Lung Assist as a Bridge to Medical Therapy in a Teenager With Pulmonary Arterial Hypertension and Partial Anomalous Pulmonary Venous Return. Can J Cardiol. 2020; 36(11):1831.e7-1831.e9. DOI: 10.1016/j.cjca.2020.06.001. View

17.

Spector L, Menk J, Knight J, McCracken C, Thomas A, Vinocur J . Trends in Long-Term Mortality After Congenital Heart Surgery. J Am Coll Cardiol. 2018; 71(21):2434-2446. PMC: 5978758. DOI: 10.1016/j.jacc.2018.03.491. View

18.

Kadari A, Lu M, Li M, Sekaran T, Thummer R, Guyette N . Excision of viral reprogramming cassettes by Cre protein transduction enables rapid, robust and efficient derivation of transgene-free human induced pluripotent stem cells. Stem Cell Res Ther. 2014; 5(2):47. PMC: 4055111. DOI: 10.1186/scrt435. View

19.

Bush B, Tobias J, Lin C, Ruda J, Jatana K, Essig G . Postoperative bradycardia following adenotonsillectomy in children: Does intraoperative administration of dexmedetomidine play a role?. Int J Pediatr Otorhinolaryngol. 2017; 104:210-215. DOI: 10.1016/j.ijporl.2017.11.025. View

20.

Pei J, Wang F, Pei S, Bai R, Cong X, Nie Y . Hydrogen Sulfide Promotes Cardiomyocyte Proliferation and Heart Regeneration ROS Scavenging. Oxid Med Cell Longev. 2020; 2020:1412696. PMC: 7261318. DOI: 10.1155/2020/1412696. View