scholarly journals MKP-1 Overexpression Reduces Postischemic Myocardial Damage through Attenuation of ER Stress and Mitochondrial Damage

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xiaoling Hou ◽  
Lijun Li ◽  
Si Chen ◽  
Cheng Ge ◽  
Mingzhi Shen ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Function ◽  
Myocardial Damage ◽  
Mitogen Activated Protein Kinase ◽  
Atp Production ◽  
Stress Genes ◽  
H9c2 Cardiomyocytes ◽  
Novel Target ◽  
Induced Apoptosis ◽  
Mitochondrial Oxidative Damage

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress contribute to postischemic myocardial damage, but the upstream regulatory mechanisms have not been identified. In this study, we analyzed the role of mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) in the regulation of mitochondrial function and ER stress in hypoxic cardiomyocytes. Our results show that MKP-1 overexpression sustains viability and reduces hypoxia-induced apoptosis among H9C2 cardiomyocytes. MKP-1 overexpression attenuates ER stress and expression of ER stress genes and improves mitochondrial function in hypoxia-treated H9C2 cells. MKP-1 overexpression also increases ATP production and mitochondrial respiration and attenuates mitochondrial oxidative damage in hypoxic cardiomyocytes. Moreover, our results demonstrate that ERK and JNK are the downstream signaling targets of MKP-1 and that MKP-1 overexpression activates ERK, while it inhibits JNK. Inhibition of ERK reduces the ability of MKP-1 to preserve mitochondrial function and ER homeostasis in hypoxic cardiomyocytes. These results show that MKP-1 plays an essential role in the regulation of mitochondrial function and ER stress in hypoxic H9C2 cardiomyocytes through normalization of the ERK pathway and suggest that MKP-1 may serve as a novel target for the treatment of postischemic myocardial injury.

Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4365-4374 ◽  
Author(s):  
Chia-Ling Chen ◽  
Chiou-Feng Lin ◽  
Wen-Tsan Chang ◽  
Wei-Ching Huang ◽  
Chiao-Fang Teng ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Er Stress ◽  
P38 Mapk ◽  
De Novo ◽  
Suppressor Gene ◽  
Mitogen Activated Protein Kinase ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Induced Apoptosis ◽  
Jnk Activation

Abstract Ceramide, a tumor-suppressor lipid, is generated by sphingomyelin hydrolysis or by de novo synthesis when cells are activated by various stress stimuli as well as when cancer cells are subjected to genotoxic chemotherapy. Ceramide may modulate apoptotic signaling pathways; however, its transcription-dependent effects remain unclear. Our data showed that actinomycin D partially inhibited ceramide-induced apoptosis. Using microarray analysis, we found that ceramide up-regulated a tumor suppressor gene called thioredoxin-interacting protein (Txnip). Similarly, the chemotherapeutic agent etoposide induced Txnip expression en route to apoptosis, which was blocked by inhibitors of ceramide production. Txnip colocalized with thioredoxin and reduced its activity, which caused dissociation of thioredoxin from apoptosis signal-regulating kinase 1 (ASK1). Cells expressing ASK1 siRNA were more resistant to ceramide-induced apoptosis. Ceramide caused ASK1-regulated p38 mitogen-activated protein kinase (MAPK) and JNK activation, as well as activation of the endoplasmic reticulum (ER) stress cascade, and pharmacologic or siRNA-mediated inhibition of p38 MAPK or JNK partially reduced ceramide-induced mitochondria-mediated apoptosis. Furthermore, ceramide-induced ASK1, p38, and JNK phosphorylation and cell apoptosis were inhibited by Txnip siRNA transfection. Taken together, we show that ceramide exhibits a mechanism of transcriptional regulation involving up-regulation of Txnip expression, also induced by etoposide, which results in ASK1 activation, ER stress, and p38 and JNK phosphorylation, all leading to apoptosis.

scholarly journals The mitochondrial respiratory chain is a modulator of apoptosis

2007 ◽  
Vol 179 (6) ◽  
pp. 1163-1177 ◽  
Author(s):  
Jennifer Q. Kwong ◽  
Matthew S. Henning ◽  
Anatoly A. Starkov ◽  
Giovanni Manfredi
Keyword(s):  
Er Stress ◽  
Respiratory Chain ◽  
Electron Flux ◽  
Atp Synthesis ◽  
Mitochondrial Respiratory Chain ◽  
Dependent Manner ◽  
Atp Production ◽  
Dna Mutations ◽  
Increased Sensitivity ◽  
Induced Apoptosis

Mitochondrial dysfunction and dysregulation of apoptosis are implicated in many diseases such as cancer and neurodegeneration. We investigate here the role of respiratory chain (RC) dysfunction in apoptosis, using mitochondrial DNA mutations as genetic models. Although some mutations eliminate the entire RC, others target specific complexes, resulting in either decreased or complete loss of electron flux, which leads to impaired respiration and adenosine triphosphate (ATP) synthesis. Despite these similarities, significant differences in responses to apoptotic stimuli emerge. Cells lacking RC are protected against both mitochondrial- and endoplasmic reticulum (ER) stress–induced apoptosis. Cells with RC, but unable to generate electron flux, are protected against mitochondrial apoptosis, although they have increased sensitivity to ER stress. Finally, cells with a partial reduction in electron flux have increased apoptosis under both conditions. Our results show that the RC modulates apoptosis in a context-dependent manner independent of ATP production and that apoptotic responses are the result of the interplay between mitochondrial functional state and environmental cues.

scholarly journals Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Philma Glora Muthuraj ◽  
Prakash K. Sahoo ◽  
Madison Kraus ◽  
Taylor Bruett ◽  
Arun S. Annamalai ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Zika Virus ◽  
Morphological Changes ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Zikv Infection ◽  
Downstream Target ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

AbstractZika virus (ZIKV) infection to a pregnant woman can be vertically transmitted to the fetus via the placenta leading to Congenital Zika syndrome. This is characterized by microcephaly, retinal defects, and intrauterine growth retardation. ZIKV induces placental trophoblast apoptosis leading to severe abnormalities in the growth and development of the fetus. However, the molecular mechanism behind ZIKV-induced apoptosis in placental trophoblasts remains unclear. We hypothesize that ZIKV infection induces endoplasmic reticulum (ER) stress in the trophoblasts, and sustained ER stress results in apoptosis. HTR-8 (HTR-8/SVneo), a human normal immortalized trophoblast cell and human choriocarcinoma-derived cell lines (JEG-3 and JAR) were infected with ZIKV. Biochemical and structural markers of apoptosis like caspase 3/7 activity and percent apoptotic nuclear morphological changes, respectively were assessed. ZIKV infection in placental trophoblasts showed an increase in the levels of CHOP mRNA and protein expression, which is an inducer of apoptosis. Next, we also observed increased levels of ER stress markers such as phosphorylated forms of inositol-requiring transmembrane kinase/endoribonuclease 1α (P-IRE1α), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2α (P-eIF2α), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16–24 h of ZIKV infection in trophoblasts. Inhibition of JNK or pan-caspases using small molecule inhibitors significantly prevented ZIKV-induced apoptosis in trophoblasts. Further, JNK inhibition also reduced XBP1 mRNA splicing and viral E protein staining in ZIKV infected cells. In conclusion, the mechanism of ZIKV-induced placental trophoblast apoptosis involves the activation of ER stress and JNK activation, and the inhibition of JNK dramatically prevents ZIKV-induced trophoblast apoptosis.

scholarly journals Reg3g ameliorates Tacrolimus-induced pancreatic β cell dysfunction by restoring mitochondrial function

2021 ◽  
Author(s):  
Ming Xiang ◽  
Senlin Li ◽  
Hong Zhou ◽  
Mengyuan Xie ◽  
Zijun Zhang ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Calcium Uptake ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Atp Production ◽  
Mitochondria Membrane Potential ◽  
Cell Dysfunction ◽  
Mitochondrial Functions ◽  
Induced Apoptosis

Background and Purpose: Tacrolimus (Tac) induces pancreatic β cell dysfunction, causing new-onset diabetes mellitus (NODM) after transplantation. Reg3g is a member of the pancreatic regenerative gene family, as reported to improve type 1 diabetes by promoting β cell regeneration. Here, we aim to investigate the role and approach of Reg3g in reversing Tac-induced β cell dysfunction and NODM in mice. Experimental Approach: Circulating REG3A (the human homolog of mouse Reg3g) concentrations of patients treated with Tac after heart transplantation(HT) were detected. The glucose-stimulated insulin secretion (GSIS) and mitochondrial functions, including mitochondria membrane potential (MMP), mitochondria calcium uptake, ATP production, and oxygen consumption rate (OCR), were tested in β cells. Effects of Reg3g on Tac-induced NODM in mice were studied. Key Results: Circulating REG3A levels significantly decreased in NODM patients treated with Tac compared with those without diabetes. Tac down-regulated Reg3g via inhibiting STAT3-mediated transcription activation, while Reg3g protected against Tac-induced apoptosis of β cells. Besides, Reg3g restored GSIS suppressed by Tac in β cells via improving mitochondrial function, including increased MMP, mitochondria calcium uptake, ATP production, and OCR. Mechanically, Reg3g increased accumulation of pSTAT3(Ser727) in mitochondria by activating ERK1/2-STAT3 signaling pathway, leading to restoration of Tac-caused mitochondrial impairment. Moreover, Reg3g overexpression effectively ameliorated Tac-induced NODM in mice. Conclusion and Implications: Reg3g ameliorates Tac-induced pancreatic β cell dysfunction by restoring mitochondrial function via a pSTAT3(Ser727)-dependent way. Our observations identify a novel Reg3g-involved mechanism underlying the augmented incidence of Tac-induced NODM and reveal that Reg3g ameliorates Tac-induced β cell dysfunction.

scholarly journals Emodin-Induced Oxidative Inhibition of Mitochondrial Function Assists BiP/IRE1α/CHOP Signaling-Mediated ER-Related Apoptosis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Li-zhen Qiu ◽  
Lan-xin Yue ◽  
Yu-hao Ni ◽  
Wei Zhou ◽  
Cong-shu Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Ros Generation ◽  
Redox Imbalance ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
L02 Cells

Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1α/CHOP signaling pathway, followed by ER Ca2+ release and cytoplasmic Ca2+ overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca2+ release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.

scholarly journals 5-ALA Attenuates the Palmitic Acid-Induced ER Stress and Apoptosis in Bovine Mammary Epithelial Cells

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1183
Author(s):  
Mst Mamuna Sharmin ◽  
Md Aminul Islam ◽  
Itsuki Yamamoto ◽  
Shin Taniguchi ◽  
Shinichi Yonekura
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Palmitic Acid ◽  
Er Stress ◽  
Aminolevulinic Acid ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Protective Effects ◽  
Bovine Mammary Epithelial Cells ◽  
Induced Apoptosis

The conservation of mammary gland physiology by maintaining the maximum number of mammary epithelial cells (MECs) is of the utmost importance for the optimum amount of milk production. In a state of negative energy balance, palmitic acid (PA) reduces the number of bovine MECs. However, there is no effective strategy against PA-induced apoptosis of MECs. In the present study, 5-aminolevulinic acid (5-ALA) was established as a remedial agent against PA-induced apoptosis of MAC-T cells (an established line of bovine MECs). In PA-treated cells, the apoptosis-related genes BCL2 and BAX were down- and upregulated, respectively. The elevated expression of major genes of the unfolded protein response (UPR), such as CHOP, a proapoptotic marker (C/EBP homologous protein), reduced the viability of PA-treated MAC-T cells. In contrast, 5-ALA pretreatment increased and decreased BCL2 and BAX expression, respectively. Moreover, cleaved caspase-3 protein expression was significantly reduced in the 5-ALA-pretreated group in comparison with the PA group. The downregulation of major UPR-related genes, including CHOP, extended the viability of MAC-T cells pretreated with 5-ALA and also reduced the enhanced intensity of the PA-induced expression of phospho-protein kinase R-like ER kinase. Moreover, the enhanced expression of HO-1 (antioxidant gene heme oxygenase) by 5-ALA reduced PA-induced oxidative stress (OxS). HO-1 is not only protective against OxS but also effective against ER stress. Collectively, these findings offer new insights into the protective effects of 5-ALA against PA-induced apoptosis of bovine MECs.

scholarly journals Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis

2021 ◽  
Vol 22 (9) ◽  
pp. 4538
Author(s):  
Helena Kratochvílová ◽  
Miloš Mráz ◽  
Barbora J. Kasperová ◽  
Daniel Hlaváček ◽  
Jakub Mahrík ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Cardiac Surgery ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Mrna Expression ◽  
Coronary Atherosclerosis ◽  
Stress Genes ◽  
Valvular Surgery

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

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.

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