Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury (Review)

Ruan, Yongxue; Zeng, Jingjing; Jin, Qike; Chu, Maoping; Ji, Kangting; Wang, Zhongyu; Li, Lei

doi:10.3892/etm.2020.9398

“…The ER, under physiological conditions, regulates many biological processes, including protein folding, assembly, modification and secretion, Ca 2+ homeostasis, and lipid synthesis [ 123 , 124 ]. However, when exposed to pathologic conditions, like ROS exposure, Ca 2+ overload, deficiency of glucose and nutrient supply, and ATP depletion, homeostasis is impaired with the accumulation of unfolded/misfolded proteins, as described above [ 87 , 88 , 123 ]. RI, impaired autopha/RI, the unfolded protein response and/or ER-initiated apoptosis is likely to be triggered by both the depletion of oxygen and energy substrates and the subsequent sudden increase in oxygen free radicals [ 125 ].…”

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

¹

,

Lu

²

,

Xin

³

et al. 2021

Oxidative Medicine and Cellular Longevity

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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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“…But what is the possible mechanism for that? Growing evidences from experimental and clinical research indicate that ER Stress is involved in several processes of cardiovascular disease such as atherosclerosis, ischemic heart disease and hypertrophic cardiomyopathy [29][30][31]. Therefore, our study assumed that ER Stress might be involved in CRT aggravating CFs activation.…”

Section: Discussionmentioning

confidence: 82%

Overexpression of Calreticulin Promotes Cardiac Fibroblasts Activation Via Regulating IRE1 Pathway

Liu

¹

,

Zhang

²

,

Li³

et al. 2021

Preprint

0

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Calreticulin (CRT) is an endoplasmic reticulum (ER) chaperone involved in cardiac fibroblasts (CFs) activation. It has been reported that the expression of CRT increased in the process of CFs activation. However, the role of CRT in CFs activation and the mechanism is not yet fully elucidated. Therefore, we aimed to verify whether CRT was involved in CFs activation and the possible mechanism underlying this process. We found that CRT protein level was elevated in AngⅡ-induced CFs activation. Knocking down CRT by its siRNA could decrease the protein expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β), and meanwhile attenuate proliferation and migration ratio of CFs. Moreover, the proliferation and migration rates of CFs were promoted and the expression of CTGF, α-SMA and TGF-β were increased when transfection with high-titer adenovirus of CRT. In AngⅡ-induced CFs, inositol-requiring enzyme 1(IRE-1), one of the main ER pathways, was inhibited through CRT silence and activated through CRT overexpression. Overall, this study demonstrates that CRT overexpression could promote AngⅡ induced-CFs activation by activating IRE1 pathway, which could be a potential target for CFs activation.

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“…ERS has also been found to regulate the inflammatory response and the apoptosis signaling pathway through the UPR, maintaining the dynamic ER balance under normal conditions and adapting to balance induced by external stimuli [ 10 ]. Excessive or long-lasting ERS leads to impaired cell function and disease development.…”

Section: Introductionmentioning

confidence: 99%

Wenxin Granules Regulate Endoplasmic Reticulum Stress Unfolded Protein Response and Improve Ventricular Remodeling on Rats with Myocardial Infarction

Liu

¹

,

Lv

²

,

Ji

³

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. Arrhythmia after myocardial infarction is the leading cause of death in clinical heart disease. Increasing studies have shown that the response to endoplasmic reticulum (ER) stress (ERS) caused by myocardial infarction is related to prognosis and the development of arrhythmias. The unfolded protein response (UPR) could serve as an important regulatory signaling pathway following myocardial infarction. The traditional Chinese medicine Wenxin Granules improve arrhythmias following myocardial infarction, which may be related to ERS intervention and the activation of the UPR and apoptosis. We aimed to investigate the involvement of Wenxin Granules in the activation of the UPR and apoptosis following myocardial infarction. Left coronary artery ligation was established as a rat model of myocardial infarction. The rats were randomly divided into the model group, low-dose Wenxin Granule group, high-dose Wenxin Granule group, and metoprolol group. Rats with only wire insertion and no ligature were used as the sham group. Small animal ultrasound systems were used to detect changes in heart structure and function, and the electrical stimulation threshold for ventricular fibrillation was detected. The expression of glucose-regulated protein (GRP)78, activating transcription factor (ATF)6, X-box binding protein (XBP)1, protein kinase–like ER kinase (PERK), phosphorylated (p)-PERK, Bax, Bcl2, C/EBP homologous protein (CHOP), caspase 12, caspase 8, and caspase 3 were detected by western blot, and terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) was used to determine the cardiomyocyte apoptosis index. Compared with the sham group, rats in the model group displayed immediate ST-segment elevation and pathological Q waves after 24 hours. After 2 weeks, the left ventricular (LV) anterior wall thickness (LVAW) became thinner, and the inner diameter (LVID) increased. The end-diastolic LVAW (LVAWd), end-systolic LVAW (LVAWs), ejection fraction (EF), and fractional shortening (FS) were significantly reduced ( P < 0.01 ), whereas the LVIDd, LVIDs, diastolic LV volume (LV Vold), and systolic LV volume (LV Vols) significantly increased ( P < 0.01 ). The ventricular fibrillation threshold decreased significantly ( P < 0.01 ). ERS proteins GRP78, p-PERK, PERK, ATF6, and XBP1 and apoptotic proteins CHOP, Bax, caspase 12, caspase 8, and caspase 3 significantly increased ( P < 0.01 , P < 0.05 ), whereas Bcl-2 expression and the Bcl-2/Bax ratio decreased ( P < 0.01 ). Compared with the sham group, LVAWd, LVAWs, FS, and Bcl-2 protein expression were significantly increased in the low-dose Wenxin Granule group ( P < 0.01 , P < 0.05 ), and p-PERK and ATF6 decreased ( P < 0.01 , P < 0.05 ). Compared with the sham group, LVAWd, LVAWs, EF, FS, and the ventricular fibrillation threshold significantly increased in the high-dose Wenxin Granule and metoprolol groups ( P < 0.01 , P < 0.05 ), whereas LVIDs, LV Vols, and ERS proteins were significantly decreased ( P < 0.01 , P < 0.05 ). CHOP, Bax, caspase 12, caspase 8, and caspase 3 protein expression decreased in the Wenxin Granule group ( P < 0.01 , P < 0.05 ), whereas Bcl-2 and the Bcl-2/Bax ratio increased ( P < 0.01 , P < 0.05 ). LVIDd and Bax decreased in the metoprolol group ( P < 0.01 , P < 0.05 ), and the Bcl-2/Bax ratio increased ( P < 0.05 ). The cardiomyocyte apoptosis index values for the low- and high-dose Wenxin Granule and metoprolol groups were significantly reduced ( P < 0.05 ). This study suggested that the UPR is an essential mechanism underlying pathological injury after myocardial infarction. Wenxin Granule treatment can improve ventricular remodeling and cardiac function and inhibit arrhythmia by preventing excessive ERS from activating the UPR and apoptosis.

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Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury (Review)

Cited by 35 publications

References 163 publications

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

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

Overexpression of Calreticulin Promotes Cardiac Fibroblasts Activation Via Regulating IRE1 Pathway

Wenxin Granules Regulate Endoplasmic Reticulum Stress Unfolded Protein Response and Improve Ventricular Remodeling on Rats with Myocardial Infarction

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