Inhibition of TGFβ‐activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression

Background: Myocardial infarction (MI) is a common cause of death worldwide. It is characterized by coronary artery occlusion that causes ischemia and hypoxia of myocardial cells, leading to irreversible myocardial damage. Materials and Methods: To explore potential targets for treatment of MI, we reorganized and analyzed two microarray datasets (GSE4648 and GSE775). The GEO2R tool was used to screen for differentially expressed genes (DEGs) between infarcted and normal myocardium. We used the Database for Annotation, Visualization and Integrated Discovery (DAVID) to perform Gene Ontology functional annotation analysis (GO analysis) and the Kyoto Encyclopedia of Genes and Genomes for pathway enrichment analysis (KEGG analysis). We examined protein-protein interactions to characterize the relationship between differentially expressed genes, and we screened potential hub genes according to the degree of connection. PCR and Western blotting were used to identify the core genes. Results: At different times of infarction, a total of 35 genes showed upregulation at all times; however, none of the genes showed downregulation at all 3 times. Similarly, 10 hub genes with high degrees of connectivity were identified. In vivo and in vitro experiments suggested that expression levels of MMP-9 increased at various times after myocardial infarction and that expression increased in a variety of cells simultaneously. Conclusion: Expression levels of MMP-9 increase throughout the course of acute myocardial infarction, and this expression has both positive and negative sides. Further studies are needed to explore the role of MMP-9 in MI treatment. The potential values of Il6,

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“…The method was previously described by our group. 11 The macrophages were RAW264.7. Mouse coronary endothelial cells were purchased from ATCC.…”

Section: Methodsmentioning

confidence: 99%

<p>Screening and Identification of Potential Hub Genes in Myocardial Infarction Through Bioinformatics Analysis</p>

Xue

Qian

et al. 2020

CIA

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“…Apoptosis induced by endoplasmic reticulum stress. RI, impaired autopha/RI, deficiency of glucose and nutrient supply, ATP depletion, ROS accumulation, and destruction of Ca 2+ homoeostasis interfere with endoplasmic reticulum (ER) function, causing unfolded protein response with unfolded/misfolded protein accumulation, the condition referred to as ER stress [ 87 , 88 ]. Numerous studies have indicated the association between ER stress and cardiomyocyte apoptosis [ 89 ].…”

Section: Pathways Through Which Oxidative Stress Causes Myocardial Reperfusion Injurymentioning

confidence: 99%

“…Numerous studies have indicated the association between ER stress and cardiomyocyte apoptosis [ 89 ]. Prolonged and/or excessive ER stress has been reported to induce ER-related apoptosis with increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP) and the activation of caspase-12 [ 87 , 90 ]. Simultaneously, ER stress was thought to disrupt the redox balance, causing ROS accumulation and mitochondria dysfunction, finally aggravating cardiomyocyte apoptosis [ 90 ].…”

Section: Pathways Through Which Oxidative Stress Causes Myocardial Reperfusion Injurymentioning

confidence: 99%

Role of Oxidative Stress in Reperfusion following Myocardial Ischemia and Its Treatments

Xiang

Xin

et al. 2021

Oxidative Medicine and Cellular Longevity

138

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Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress is one of the most important pathological mechanisms in reperfusion injury, which causes apoptosis, autophagy, inflammation, and some other damage in cardiomyocytes through multiple pathways, thus causing irreversible cardiomyocyte damage and cardiac dysfunction. This article reviews the pathological mechanisms of oxidative stress involved in reperfusion injury and the interventions for different pathways and targets, so as to form systematic treatments for oxidative stress-induced myocardial reperfusion injury and make up for the lack of monotherapy.

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“…Recent studies showed that multiple mechanisms are involved during the process of myocardial I/R injury, such as inflammation, apoptosis, intracellular calcium overload, endothelial dysfunction, reactive oxygen species, and endoplasmic reticulum stress (ERS). [3][4][5][6][7][8] Under physiological conditions, the endoplasmic reticulum serves many essential roles in cell function, including protein synthesis, protein folding, calcium homoeostasis, and lipid metabolism. 8,9 Under a stress condition such as the myocardial I/R process, the endoplasmic reticulum homoeostasis is disrupted, and unfolded or misfolded proteins accumulates, leading to the prolonged unfolded protein response (UPR) during ERS.…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling

Yu¹,

Wang²,

Song³

et al. 2021

JIR

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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 α2-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 α2 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.

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Inhibition of TGFβ‐activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression

Cited by 20 publications

References 47 publications

<p>Screening and Identification of Potential Hub Genes in Myocardial Infarction Through Bioinformatics Analysis</p>

<p>Screening and Identification of Potential Hub Genes in Myocardial Infarction Through Bioinformatics Analysis</p>

Role of Oxidative Stress in Reperfusion following Myocardial Ischemia and Its Treatments

Dexmedetomidine Attenuates Ischemia/Reperfusion-Induced Myocardial Inflammation and Apoptosis Through Inhibiting Endoplasmic Reticulum Stress Signaling

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