Abstract 590: Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masafumi Myoishi ◽  
Testuo Minamino ◽  
Masafumi Kitakaze
Keyword(s):  
Endoplasmic Reticulum ◽  
Coronary Artery ◽  
Er Stress ◽  
Atherosclerotic Plaques ◽  
Coronary Syndrome ◽  
Er Chaperone ◽  
Unstable Plaques ◽  
Induced Apoptosis ◽  
Stress Dependent ◽  
Dependent Pathway

Background Endoplasmic reticulum (ER) responds to various stresses by up-regulation of ER chaperones, and prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear. Methods and Results We obtained 152 coronary artery segments at autopsy and 40 atherectomy specimens from 71 and 40 patients, respectively . Smooth muscle cells (SMCs) and macrophages in the fibrous caps of thin cap atheroma and ruptured plaques, but not in the fibrous caps of thick cap atheroma and fibrous plaques, showed a marked increase in the expression of ER chaperone and numbers of apoptotic cells. ER chaperones also expressed higher in atherectomy specimens from patients with unstable angina pectoris than with stable angina. To explore the plausible molecular mechanism of activation of ER stress and the mechanistic link to apoptosis, we investigated plaque lipids such as oxysterols. Among oxysterols, expression of 7-ketocholesterol was increased in the fibrous caps of thin cap atheroma compared with thick cap atheroma. Treatment of either cultured coronary artery SMCs or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, while these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP (a transcription factor induced by ER stress)-dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by siRNA decreased ER stress-dependent death of cultured coronary artery SMCs and THP-1 cells. Conclusions Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of SMCs and macrophages may contribute to plaque vulnerability.

scholarly journals Characterization of Endoplasmic Reticulum (ER) in Human Pluripotent Stem Cells Revealed Increased Susceptibility to Cell Death upon ER Stress

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1078
Author(s):  
Tae Won Ha ◽  
Ji Hun Jeong ◽  
HyeonSeok Shin ◽  
Hyun Kyu Kim ◽  
Jeong Suk Im ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Pluripotent Stem Cells ◽  
Meta Analysis ◽  
Embryonic Stem ◽  
Structural Features ◽  
Human Pluripotent Stem Cells ◽  
Differentiated Cells ◽  
Induced Apoptosis

Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have a well-orchestrated program for differentiation and self-renewal. However, the structural features of unique proteostatic-maintaining mechanisms in hPSCs and their features, distinct from those of differentiated cells, in response to cellular stress remain unclear. We evaluated and compared the morphological features and stress response of hPSCs and fibroblasts. Compared to fibroblasts, electron microscopy showed simpler/fewer structures with fewer networks in the endoplasmic reticulum (ER) of hPSCs, as well as lower expression of ER-related genes according to meta-analysis. As hPSCs contain low levels of binding immunoglobulin protein (BiP), an ER chaperone, thapsigargin treatment sharply increased the gene expression of the unfolded protein response. Thus, hPSCs with decreased chaperone function reacted sensitively to ER stress and entered apoptosis faster than fibroblasts. Such ER stress-induced apoptotic processes were abolished by tauroursodeoxycholic acid, an ER-stress reliever. Hence, our results revealed that as PSCs have an underdeveloped structure and express fewer BiP chaperone proteins than somatic cells, they are more susceptible to ER stress-induced apoptosis in response to stress.

scholarly journals Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells

2021 ◽  
Vol 22 (20) ◽  
pp. 10951
Author(s):  
Chong-Sun Khoi ◽  
Yu-Wen Lin ◽  
Jia-Huang Chen ◽  
Biing-Hui Liu ◽  
Tzu-Yu Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Ochratoxin A ◽  
Reactive Oxygen ◽  
Underlying Mechanism ◽  
Oxygen Species ◽  
Food And Feed ◽  
Renal Proximal Tubular Cells ◽  
Induced Apoptosis

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.

scholarly journals Licochalcone A-Induced Human Bladder Cancer T24 Cells Apoptosis Triggered by Mitochondria Dysfunction and Endoplasmic Reticulum Stress

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Xuan Yuan ◽  
Defang Li ◽  
Hong Zhao ◽  
Jiangtao Jiang ◽  
Penglong Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Parp Cleavage ◽  
Ros Generation ◽  
Human Bladder Cancer ◽  
Human Bladder ◽  
Licochalcone A ◽  
T24 Cells ◽  
Stress Dependent

Licochalcone A (LCA), a licorice chalconoid, is considered to be a bioactive agent with chemopreventive potential. This study investigated the mechanisms involved in LCA-induced apoptosis in human bladder cancer T24 cells. LCA significantly inhibited cells proliferation, increased reactive oxygen species (ROS) levels, and caused T24 cells apoptosis. Moreover, LCA induced mitochondrial dysfunction, caspase-3 activation, and poly-ADP-ribose polymerase (PARP) cleavage, which displayed features of mitochondria-dependent apoptotic signals. Besides, exposure of T24 cells to LCA triggered endoplasmic reticulum (ER) stress; as indicated by the enhancement in 78 kDa glucose-regulated protein (GRP 78), growth arrest and DNA damage-inducible gene 153/C/EBP homology protein (GADD153/CHOP) expression, ER stress-dependent apoptosis is caused by the activation of ER-specific caspase-12. All the findings from our study suggest that LCA initiates mitochondrial ROS generation and induces oxidative stress that consequently causes T24 cell apoptosis via the mitochondria-dependent and the ER stress-triggered signaling pathways.

scholarly journals Chemotherapy Resistance Explained through Endoplasmic Reticulum Stress-Dependent Signaling

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 338 ◽  
Author(s):  
Entaz Bahar ◽  
Ji-Ye Kim ◽  
Hyonok Yoon
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Protein Quality ◽  
Chemotherapy Resistance ◽  
Persistent Problem ◽  
Stress Dependent ◽  
The Relationship

Cancers cells have the ability to develop chemotherapy resistance, which is a persistent problem during cancer treatment. Chemotherapy resistance develops through different molecular mechanisms, which lead to modification of the cancer cells signals needed for cellular proliferation or for stimulating an immune response. The endoplasmic reticulum (ER) is an important organelle involved in protein quality control, by promoting the correct folding of protein and ER-mediated degradation of unfolded or misfolded protein, namely, ER-associated degradation. Disturbances of the normal ER functions causes an accumulation of unfolded or misfolded proteins in the ER lumen, resulting in a condition called “ER stress (ERS).” ERS triggers the unfolded protein response (UPR)—also called the ERS response (ERSR)—to restore homeostasis or activate cell death. Although the ERSR is one emerging potential target for chemotherapeutics to treat cancer, it is also critical for chemotherapeutics resistance, as well. However, the detailed molecular mechanism of the relationship between the ERSR and tumor survival or drug resistance remains to be fully understood. In this review, we aim to describe the most vital molecular mechanism of the relationship between the ERSR and chemotherapy resistance. Moreover, the review also discusses the molecular mechanism of ER stress-mediated apoptosis on cancer treatments.

scholarly journals Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78-Loaded Extracellular Vesicles

2020 ◽  
Author(s):  
Malgorzata Furmanik ◽  
Rick van Gorp ◽  
Meredith Whitehead ◽  
Sadia Ahmad ◽  
Jayanta Bordoloi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Er Stress ◽  
Vascular Calcification ◽  
Bone Mineralization ◽  
Extracellular Vesicle ◽  
Dependent Manner ◽  
The Matrix ◽  
Stress Dependent

Objective: Vascular calcification is common among aging populations and mediated by vascular smooth muscle cells (VSMCs). The endoplasmic reticulum (ER) is involved in protein folding and ER stress has been implicated in bone mineralization. The role of ER stress in VSMC-mediated calcification is less clear. Approach and Results: mRNA expression of the ER stress markers PERK (PKR (protein kinase RNA)-like ER kinase), ATF (activating transcription factor) 4, ATF6, and Grp78 was detectable in human vessels with levels of PERK decreased in calcified plaques compared to healthy vessels. Protein deposition of Grp78/Grp94 was increased in the matrix of calcified arteries. Induction of ER stress accelerated human primary VSMC-mediated calcification, elevated expression of some osteogenic markers (Runx2, Osterix, ALP, BSP, and OPG), and decreased expression of SMC markers. ER stress potentiated extracellular vesicle (EV) release via SMPD3. EVs from ER stress-treated VSMCs showed increased Grp78 levels and calcification. Electron microscopy confirmed the presence of Grp78/Grp94 in EVs. siRNA knock-down of Grp78 decreased calcification. Warfarin-induced Grp78 and ATF4 expression in rat aortas and VSMCs and increased calcification in an ER stress-dependent manner via increased EV release. Conclusions: ER stress induces vascular calcification by increasing release of Grp78-loaded EVs. Our results reveal a novel mechanism of action of warfarin, involving increased EV release via the PERK-ATF4 pathway, contributing to calcification. This study is the first to show that warfarin induces ER stress and to link ER stress to cargo loading of EVs.

scholarly journals Japanese Encephalitis Virus Induces Apoptosis and Encephalitis by Activating the PERK Pathway

2019 ◽  
Vol 93 (17) ◽  
Author(s):  
Qianruo Wang ◽  
Xiu Xin ◽  
Ting Wang ◽  
Jiawu Wan ◽  
Yangtao Ou ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Encephalitis Virus ◽  
Protein Kinase R ◽  
Apoptosis Pathway ◽  
Stress Sensor ◽  
Sensor Protein ◽  
Induced Apoptosis

ABSTRACTAccumulated evidence demonstrates that Japanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, the precise role of PERK in JEV-induced apoptosis and encephalitis remains unknown. Here, we report that JEV infection activates the PERK-ATF4-CHOP apoptosis pathway bothin vitroandin vivo. PERK activation also promotes the formation of stress granule, which in turn represses JEV-induced apoptosis. However, PERK inhibitor reduces apoptosis, indicating that JEV-activated PERK predominantly induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway. Among JEV proteins that have been reported to induce ER stress, only JEV NS4B can induce PERK activation. PERK has been reported to form an active molecule by dimerization. The coimmunoprecipitation assay shows that NS4B interacts with PERK. Moreover, glycerol gradient centrifugation shows that NS4B induces PERK dimerization. Both the LIG-FHA and the LIG-WD40 domains within NS4B are required to induce PERK dimerization, suggesting that JEV NS4B pulls two PERK molecules together by simultaneously interacting with them via different motifs. PERK deactivation reduces brain cell damage and encephalitis during JEV infection. Furthermore, expression of JEV NS4B is sufficient to induce encephalitis via PERK in mice, indicating that JEV activates PERK primarily via its NS4B to cause encephalitis. Taken together, our findings provide a novel insight into JEV-caused encephalitis.IMPORTANCEJapanese encephalitis virus (JEV) infection triggers endoplasmic reticulum (ER) stress and neuron apoptosis. ER stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) has been reported to induce apoptosis under acute or prolonged ER stress. However, whether the PERK pathway of ER stress response plays important roles in JEV-induced apoptosis and encephalitis remains unknown. Here, we found that JEV infection activates ER stress sensor PERK in neuronal cells and mouse brains. PERK activation induces apoptosis via the PERK-ATF4-CHOP apoptosis pathway upon JEV infection. Among the JEV proteins prM, E, NS1, NS2A, NS2B, and NS4B, only NS4B activates PERK. Moreover, activated PERK participates in apoptosis and encephalitis induced by JEV and NS4B. These findings provide a novel therapeutic approach for JEV-caused encephalitis.

Sirtuin-3 (SIRT3) protects pancreatic β-cells from endoplasmic reticulum (ER) stress-induced apoptosis and dysfunction

2016 ◽  
Vol 420 (1-2) ◽  
pp. 95-106 ◽  
Author(s):  
Hao-Hao Zhang ◽  
Xiao-Jun Ma ◽  
Li-Na Wu ◽  
Yan-Yan Zhao ◽  
Peng-Yu Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Sirtuin 3 ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Induced Apoptosis

Involvement of TR3/Nur77 translocation to the endoplasmic reticulum in ER stress-induced apoptosis

2007 ◽  
Vol 313 (13) ◽  
pp. 2833-2844 ◽  
Author(s):  
Bin Liang ◽  
Xuhong Song ◽  
Gefei Liu ◽  
Rui Li ◽  
Jianping Xie ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Induced Apoptosis

scholarly journals Activation of endoplasmic reticulum stress mediates oxidative stress–induced apoptosis of granulosa cells in ovaries affected by endometrioma

2019 ◽  
Vol 26 (1) ◽  
pp. 40-52 ◽  
Author(s):  
Chisato Kunitomi ◽  
Miyuki Harada ◽  
Nozomi Takahashi ◽  
Jerilee M K Azhary ◽  
Akari Kusamoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Granulosa Cells ◽  
Ovarian Function ◽  
Stress Sensor ◽  
Local Factor ◽  
High Oxidative Stress ◽  
Induced Apoptosis ◽  
Sensor Proteins

Abstract Endometriosis exerts detrimental effects on ovarian physiology and compromises follicular health. Granulosa cells from patients with endometriosis are characterized by increased apoptosis, as well as high oxidative stress. Endoplasmic reticulum (ER) stress, a local factor closely associated with oxidative stress, has emerged as a critical regulator of ovarian function. We hypothesized that ER stress is activated by high oxidative stress in granulosa cells in ovaries with endometrioma and that this mediates oxidative stress–induced apoptosis. Human granulosa-lutein cells (GLCs) from patients with endometrioma expressed high levels of mRNAs associated with the unfolded protein response (UPR). In addition, the levels of phosphorylated ER stress sensor proteins, inositol-requiring enzyme 1 (IRE1) and double-stranded RNA-activated protein kinase-like ER kinase (PERK), were elevated in granulosa cells from patients with endometrioma. Given that ER stress results in phosphorylation of ER stress sensor proteins and induces UPR factors, these findings indicate that these cells were under ER stress. H2O2, an inducer of oxidative stress, increased expression of UPR-associated mRNAs in cultured human GLCs, and this effect was abrogated by pretreatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor in clinical use. Treatment with H2O2 increased apoptosis and the activity of the pro-apoptotic factors caspase-8 and caspase-3, both of which were attenuated by TUDCA. Our findings suggest that activated ER stress induced by high oxidative stress in granulosa cells in ovaries with endometrioma mediates apoptosis of these cells, leading to ovarian dysfunction in patients with endometriosis.

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