Dexmedetomidine Preconditioning Reduces Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting the PERK Pathway

Overview

Journal Arq Bras Cardiol

Specialty Cardiology & Vascular Diseases

Date 2021 Oct 13

PMID 34644786

Citations 5

Authors

Yujiao Chen

Song Cao

Hui Chen

Cunzhi Yin

Xinpeng Xu

ZaiQun Yang

Affiliations

Soon will be listed here.

Abstract

Background: Ischemic heart disease has attracted much attention due to its high mortality rates, treatment costs and the increasing morbidity in the young population. Strategies for reperfusion have reduced mortality. However, reperfusion can lead to cardiomyocyte death and subsequent irreversible myocardial damage. At present, the timely and targeted treatment of ischemia-reperfusion (I/R) injury is often lacking.

Objectives: To evaluate if dexmedetomidine (DEX) has a protective effect in myocardiual I/R and explore the possible mechanism behind it.

Methods: Rat hearts were perfused with a Langendorff perfusion system, and randomly assigned to five groups: control group, perfused with Krebs-Henseleit (K-H) solution for 205 minutes without ischemia; and four test groups that underwent 40 minutes of global ischemia and 120 min of reperfusion. The DEX group, the yohimbine (YOH) group and the DEX + YOH group were perfused with DEX (10 nM), YOH (1 μM) or the combination of DEX and YOH prior to reperfusion, respectively. Cardiac hemodynamics, myocardial infarct size, and myocardial histology were evaluated. The expression of glucose-related protein 78 (GRP78), protein kinase R-like ER kinase (PERK), phosphorylated PERK, eukaryotic initiation factor 2α (eIF2α), phosphorylated eIF2α, activating transcription factor 4 (ATF4), and CCAAT/enhancer-binding protein homologous protein (CHOP) were assessed. P<0.05 was considered to indicate a statistically significant difference.

Results: DEX preconditioning improved the cardiac function of I/R hearts, reduced myocardial infarction, myocardial apoptosis, and the expression of GRP78, p-PERK, eIF2α, p-eIF2α, ATF4 and CHOP.

Conclusions: DEX pretreatment reduced myocardial I/R injury by suppressing apoptosis, which was induced by the PERK pathway.

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References

Qing G, Li B, Vu A, Skuli N, Walton Z, Liu X . ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cancer Cell. 2012; 22(5):631-44. PMC: 3510660. DOI: 10.1016/j.ccr.2012.09.021. View

Ibanez B, Heusch G, Ovize M, Van de Werf F . Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015; 65(14):1454-71. DOI: 10.1016/j.jacc.2015.02.032. View

Glembotski C . Endoplasmic reticulum stress in the heart. Circ Res. 2007; 101(10):975-84. DOI: 10.1161/CIRCRESAHA.107.161273. View

Tabas I, Ron D . Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011; 13(3):184-90. PMC: 3107571. DOI: 10.1038/ncb0311-184. View

Qiu B, Hu S, Liu L, Chen M, Wang L, Zeng X . CART attenuates endoplasmic reticulum stress response induced by cerebral ischemia and reperfusion through upregulating BDNF synthesis and secretion. Biochem Biophys Res Commun. 2013; 436(4):655-9. DOI: 10.1016/j.bbrc.2013.05.142. View

Liu Z, Lv Y, Zhao N, Guan G, Wang J . Protein kinase R-like ER kinase and its role in endoplasmic reticulum stress-decided cell fate. Cell Death Dis. 2015; 6:e1822. PMC: 4650730. DOI: 10.1038/cddis.2015.183. View

Vaughn L, Snee B, Patel R . Inhibition of PKR protects against tunicamycin-induced apoptosis in neuroblastoma cells. Gene. 2013; 536(1):90-6. DOI: 10.1016/j.gene.2013.11.074. View

Venn M, Newman J, Grounds M . A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Intensive Care Med. 2003; 29(2):201-7. DOI: 10.1007/s00134-002-1579-9. View

Park J, Lucchesi B . Mechanisms of myocardial reperfusion injury. Ann Thorac Surg. 1999; 68(5):1905-12. DOI: 10.1016/s0003-4975(99)01073-5. View

10.

Wu H, Ye M, Yang J, Ding J . Modulating endoplasmic reticulum stress to alleviate myocardial ischemia and reperfusion injury from basic research to clinical practice: A long way to go. Int J Cardiol. 2016; 223:630-631. DOI: 10.1016/j.ijcard.2016.08.266. View

11.

Yu L, Li B, Zhang M, Jin Z, Duan W, Zhao G . Melatonin reduces PERK-eIF2α-ATF4-mediated endoplasmic reticulum stress during myocardial ischemia-reperfusion injury: role of RISK and SAFE pathways interaction. Apoptosis. 2016; 21(7):809-24. DOI: 10.1007/s10495-016-1246-1. View

12.

Degabriele N, Griesenbach U, Sato K, Post M, Zhu J, Williams J . Critical appraisal of the mouse model of myocardial infarction. Exp Physiol. 2004; 89(4):497-505. DOI: 10.1113/expphysiol.2004.027276. View

13.

Cao S, Liu Y, Wang H, Mao X, Chen J, Liu J . Ischemic postconditioning influences electron transport chain protein turnover in Langendorff-perfused rat hearts. PeerJ. 2016; 4:e1706. PMC: 4768691. DOI: 10.7717/peerj.1706. View

14.

Su N, Kilberg M . C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene. J Biol Chem. 2008; 283(50):35106-17. PMC: 2596379. DOI: 10.1074/jbc.M806874200. View

15.

Liu X, Zhang Z, Sun S, Wu X . Ischemic postconditioning protects myocardium from ischemia/reperfusion injury through attenuating endoplasmic reticulum stress. Shock. 2008; 30(4):422-7. DOI: 10.1097/SHK.0b013e318164ca29. View

16.

Locker N, Easton L, Lukavsky P . HCV and CSFV IRES domain II mediate eIF2 release during 80S ribosome assembly. EMBO J. 2007; 26(3):795-805. PMC: 1794401. DOI: 10.1038/sj.emboj.7601549. View

17.

Xu Q, Chen C, Lin A, Xie Y . Endoplasmic reticulum stress-mediated membrane expression of CRT/ERp57 induces immunogenic apoptosis in drug-resistant endometrial cancer cells. Oncotarget. 2017; 8(35):58754-58764. PMC: 5601689. DOI: 10.18632/oncotarget.17678. View

18.

Cao J, Dai D, Yao L, Yu H, Ning B, Zhang Q . Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway. Mol Cell Biochem. 2012; 364(1-2):115-29. DOI: 10.1007/s11010-011-1211-9. View

19.

Thompson S, Gulyas K, Sarnow P . Internal initiation in Saccharomyces cerevisiae mediated by an initiator tRNA/eIF2-independent internal ribosome entry site element. Proc Natl Acad Sci U S A. 2001; 98(23):12972-7. PMC: 60809. DOI: 10.1073/pnas.241286698. View

20.

Bi X, Zhang G, Wang X, Nguyen C, May H, Li X . Endoplasmic Reticulum Chaperone GRP78 Protects Heart From Ischemia/Reperfusion Injury Through Akt Activation. Circ Res. 2018; 122(11):1545-1554. PMC: 5970094. DOI: 10.1161/CIRCRESAHA.117.312641. View