Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling
Received 18 November 2020
Accepted for publication 16 March 2021
Published 31 March 2021 Volume 2021:14 Pages 1217—1233
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Professor Ning Quan
Yu-fan Yang,1,* Hui Wang,1,2,* Nan Song,1,* Ya-hui Jiang,1 Jun Zhang,1 Xiao-wen Meng,1 Xiao-mei Feng,3,4 Hong Liu,5 Ke Peng,1 Fu-hai Ji1
1Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 2Department of Anesthesiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China; 3Department of Anesthesiology, University of Utah Health, Salt Lake City, UT, USA; 4Transitional Residency Program, Intermountain Medical Center, Murray, UT, USA; 5Department of Anesthesiology and Pain Medicine, University of California Davis Health, Sacramento, CA, USA
*These authors contributed equally to this work
Correspondence: Ke Peng; Fu-hai Ji
Department of Anesthesiology, First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, People’s Republic of China
Email [email protected]; [email protected]
Background: Endoplasmic reticulum stress (ERS)-mediated myocardial inflammation and apoptosis plays an important role in myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has been used clinically with sedative, analgesic, and anti-inflammatory properties. This study aimed to determine the effects of dexmedetomidine pretreatment on inflammation, apoptosis, and the expression of ERS signaling during myocardial I/R injury.
Methods: Rats underwent myocardial ischemia for 30 min and reperfusion for 6 h, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury (OGD for 12 h and reoxygenation for 3 h). Dexmedetomidine was administered prior to myocardial ischemia in rats or ODG in cardiomyocytes. In addition, the α 2-adrenergic receptor antagonist (yohimbine) or the PERK activator (CCT020312) was given prior to dexmedetomidine treatment.
Results: Dexmedetomidine pretreatment decreased serum levels of cardiac troponin I, reduced myocardial infarct size, alleviated histological structure damage, and improved left ventricular function following myocardial I/R injury in rats. In addition, dexmedetomidine pretreatment increased cell viability and reduced cytotoxicity following OGD/R injury in cardiomyocytes. Mechanistically, the cardioprotection offered by dexmedetomidine was mediated via the inhibition of inflammation and apoptosis through downregulating the expression of the ERS signaling pathway, including glucose-regulated protein 78 (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), inositol-requiring protein 1 (IRE1), and activating transcription factor 6 (ATF6). Conversely, the protective effects of dexmedetomidine were diminished by blocking the α 2 adrenergic receptors with yohimbine or promoting PERK phosphorylation with CCT020312.
Conclusion: Dexmedetomidine pretreatment protects the hearts against I/R injury via inhibiting inflammation and apoptosis through downregulation of the ERS signaling pathway. Future clinical studies are needed to confirm the cardioprotective effects of dexmedetomidine in patients at risk of myocardial I/R injury.
Keywords: myocardial ischemia/reperfusion injury, dexmedetomidine, endoplasmic reticulum stress, inflammation, apoptosis, GRP78/PERK/CHOP
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