scholarly journals Sodium 4-Phenylbutyrate Attenuates Myocardial Reperfusion Injury by Reducing the Unfolded Protein Response

2016 ◽  
Vol 22 (3) ◽  
pp. 283-292 ◽  
Author(s):  
Osamu Takatori ◽  
Soichiro Usui ◽  
Masaki Okajima ◽  
Shuichi Kaneko ◽  
Hiroshi Ootsuji ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Unfolded Protein Response ◽  
Messenger Rna ◽  
Troponin I ◽  
Ischemia Reperfusion ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: The unfolded protein response (UPR) plays a pivotal role in ischemia–reperfusion (I/R) injury in various organs such as heart, brain, and liver. Sodium 4-phenylbutyrate (PBA) reportedly acts as a chemical chaperone that reduces UPR. In the present study, we evaluated the effect of PBA on reducing the UPR and protecting against myocardial I/R injury in mice. Methods: Male C57BL/6 mice were subjected to 30-minute myocardial I/R, and were treated with phosphate-buffered saline (as a vehicle) or PBA. Results: At 4 hours after reperfusion, mice treated with PBA had reduced serum cardiac troponin I levels and numbers of apoptotic cells in left ventricles (LVs) in myocardial I/R. Infarct size had also reduced in mice treated with PBA at 48 hours after reperfusion. At 2 hours after reperfusion, UPR markers, including eukaryotic initiation of the factor 2α-subunit, activating transcription factor-6, inositol-requiring enzyme-1, glucose-regulated protein 78, CCAAT/enhancer-binding protein (C/EBP) homologous protein, and caspase-12, were significantly increased in mice treated with vehicle compared to sham-operated mice. Administration of PBA significantly reduced the I/R-induced increases of these markers. Cardiac function and dimensions were assessed at 21 days after I/R. Sodium 4-phenylbutyrate dedicated to the improvement of cardiac parameters deterioration including LV end-diastolic diameter and LV fractional shortening. Consistently, PBA reduced messenger RNA expression levels of cardiac remodeling markers such as collagen type 1α1, brain natriuretic peptide, and α skeletal muscle actin in LV at 21 days after I/R. Conclusion: Unfolded protein response mediates myocardial I/R injury. Administration of PBA reduces the UPR, apoptosis, infarct size, and preserved cardiac function. Hence, PBA may be a therapeutic option to attenuate myocardial I/R injury in clinical practice.

scholarly journals The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation

2016 ◽  
Vol 311 (5) ◽  
pp. L846-L854 ◽  
Author(s):  
Hang Nguyen ◽  
Bruce D. Uhal
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cathepsin D ◽  
Lung Epithelial Cells ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the proapoptotic cathepsin D and reducing antiapoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system. A549 cells were challenged with MG132 or SP-C BRICHOS domain mutant G100S to induce ER stress and activation of UPR pathways. The results showed that either MG132 or G100S SP-C mutation activated all three canonical pathways of the UPR (IRE1/XBP1, ATF6, and PERK/eIF2α), which led to a significant increase in cathepsin D or in TACE (an ACE-2 ectodomain shedding enzyme) and eventually caused AEC apoptosis. However, ER stress-induced AEC apoptosis could be prevented by chemical chaperone or by UPR blockers. It is also suggested that ATF6 and IRE1 pathways might play important role in regulation of angiotensin system. These data demonstrate that ER stress induces apoptosis in human AECs through mediation of UPR pathways, which in turn regulate the autocrine ANGII/ANG1-7 system. They also demonstrated that ER stress-induced AEC apoptosis can be blocked by inhibition of UPR signaling pathways.

Requirement of clusterin expression for prosurvival autophagy in hypoxic kidney tubular epithelial cells

2016 ◽  
Vol 310 (2) ◽  
pp. F160-F173 ◽  
Author(s):  
Hatem A. Alnasser ◽  
Qiunong Guan ◽  
Fan Zhang ◽  
Martin E. Gleave ◽  
Christopher Y. C. Nguan ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Light Chain ◽  
Fluorescent Protein ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Flow Cytometric Analysis ◽  
Kidney Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Cellular autophagy is a prosurvival mechanism in the kidney against ischemia-reperfusion injury (IRI), but the molecular pathways that activate the autophagy in ischemic kidneys are not fully understood. Clusterin (CLU) is a chaperone-like protein, and its expression is associated with kidney resistance to IRI. The present study investigated the role of CLU in prosurvival autophagy in the kidney. Renal IRI was induced in mice by clamping renal pedicles at 32°C for 45 min. Hypoxia in renal tubular epithelial cell (TEC) cultures was induced by exposure to a 1% O2 atmosphere. Autophagy was determined by either light chain 3-BII expression with Western blot analysis or light chain 3-green fluorescent protein aggregation with confocal microscopy. Cell apoptosis was determined by flow cytometric analysis. The unfolded protein response was determined by PCR array. Here, we showed that autophagy was significantly activated by IRI in wild-type (WT) but not CLU-deficient kidneys. Similarly, autophagy was activated by hypoxia in human proximal TECs (HKC-8) and WT mouse primary TECs but was impaired in CLU-null TECs. Hypoxia-activated autophagy was CLU dependent and positively correlated with cell survival, and inhibition of autophagy significantly promoted cell death in both HKC-8 and mouse WT/CLU-expressing TECs but not in CLU-null TECs. Further experiments showed that CLU-dependent prosurvival autophagy was associated with activation of the unfolded protein response in hypoxic kidney cells. In conclusion, these data suggest that activation of prosurvival autophagy by hypoxia in kidney cells requires CLU expression and may be a key cytoprotective mechanism of CLU in the protection of the kidney from hypoxia/ischemia-mediated injury.

Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

2020 ◽  
Vol 39 (12) ◽  
pp. 1690-1699
Author(s):  
H Yu ◽  
K Wen ◽  
X Zhou ◽  
Y Zhang ◽  
Z Yan ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Messenger Rna ◽  
Hypoxia Inducible Factor ◽  
Reproductive Organs ◽  
Pregnant Mouse ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

Abstract 261: Robust Cardioprotection Afforded by a Previously Unrecognized Link between the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Zhao V Wang ◽  
Yingfeng Deng ◽  
Ningguo Gao ◽  
Zully Pedrozo ◽  
Dan Li ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Biosynthetic Pathway ◽  
Ischemia Reperfusion ◽  
Uridine Diphosphate ◽  
Hexosamine Biosynthetic Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Rate Limiting

Background: The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in glucose metabolism and multiple diseases, regulation of the HBP remains largely undefined. Methods & Results: Here, we show that spliced Xbp1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers activation of the HBP by means of Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions known to promote O-GlcNAc modification. We go on to demonstrate that Xbp1s, acutely stimulated by ischemia/reperfusion (I/R) in heart, confers robust cardioprotection against I/R injury. We also show that HBP induction is required for this cardioprotective response. Mechanistically, HBP may mediate the adaptive branch of the UPR by activating autophagy and ER-associated degradation. Conclusion: These studies reveal that Xbp1s couples the UPR to the HBP, promoting robust cardioprotection during I/R.

Abstract 1313: Pro-atherogenic Effects Of Lipid Peroxidation Products: Role Of The Unfolded Protein Response

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Elena Vladykoskaya ◽  
Petra Haberzettl ◽  
Yonis Ahmed ◽  
Bradford G Hill ◽  
Srinivas D Sithu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Initiation Factor ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Jnk Activation

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are associated with atherosclerosis. Expression of UPR target genes such as activating transcription factor 3 (ATF3) and ATF4 is markedly increased in human atherosclerotic lesions. Staining for these proteins co-localizes with the staining with antibodies that recognize the aldehydic epitopes of oxidized LDL, suggesting that lipid-derived aldehydes could be involved in mediating ER stress and UPR. We examined the role of phospholipid aldehyde, 1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphocholine (POVPC), unsaturated lipid-derived aldehydes- 4-hydroxy, trans -2-nonenal (HNE) and acrolein in the induction of ER-stress and UPR in human aortic endothelial cells (HAEC) and human umbical vein endothelial cells (HUVEC). POVPC, HNE and acrolein (10 –25 μM) increased the phosphorylation of eIF2α (eukaryotic initiation factor-2α) by 1.5–5 fold (P<0.001) and induced its downstream effector proteins - ATF4 (1.5–3.5 fold; P<0.001) and ATF3 (4–10 fold; P<0.0001). Incubation of HAEC with these aldehydes also increased the adhesion of THP-1 cells (monocyte) to HAEC by 1.4–1.6 fold (P<0.01). Moreover, incubation of endothelial cells with POVPC increased the mRNA level of the pro-inflammatory cytokine IL-8 by >25 fold (P<0.0001). Chemical chaperone, phenyl butyric acid (PBA), diminished aldehydes-induced expression of ATF3 and ATF4 proteins, endothelial cell-monocyte adhesion and IL-8 formation by 80–95% (P<0.001). POVPC (10–25 μM) also activated JNK by (3–6 fold) in HAEC. Reduction of POVPC to its corresponding alcohol, 1-palmitoyl-2-(5-hydroxyvaleroyl)- sn -glycero-3-phosphocholine (PHVPC) inhibited JNK activation by 74 ± 14 % (P<0.001). Pharmacological inhibition of JNK, inhibited the aldehyde-induced induction of ATF3 and ATF4 proteins by 70–90 % (P<0.001) but not the phosphorylation of eIF2α, and PBA inhibited the POVPC-induced JNK activation by 85 ± 11 % (P<0.001). These data suggest that lipoprotein oxidation products activate endothelial cells in part by inducing ER-stress and their inflammatory signaling could be attenuated by chemical chaperones of protein folding.

scholarly journals Dysfunction of the Unfolded Protein Response during Global Brain Ischemia and Reperfusion

2003 ◽  
Vol 23 (4) ◽  
pp. 462-471 ◽  
Author(s):  
Rita Kumar ◽  
Gary S. Krause ◽  
Hiderou Yoshida ◽  
Kazutoshi Mori ◽  
Donald J. DeGracia
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Brain Ischemia ◽  
Messenger Rna ◽  
Ischemia And Reperfusion ◽  
Global Brain Ischemia ◽  
Compensatory Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane–bound proteins ATF6, IRE1α, and PERK. The authors simultaneously examined the activation of ATF6, IRE1α, and PERK, as well as components of downstream UPR pathways, in the rat brain after reperfusion after a 10-minute cardiac arrest. Although ATF6 was not activated, PERK was maximally activated at 10-minute reperfusion, which correlated with maximal eIF2α phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80% loss of PERK immunostaining in cortex and 50% loss in brain stem and hippocampus. PERK was degraded in vitro by μ-calpain. Although inactive IRE1α was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had been processed by removal of a 26-nt sequence. Similarly, there was no expression of the UPR effector proteins 55-kd XBP-1, CHOP, or ATF4. These data indicate that there is dysfunction in several key components of the UPR that abrogate the effects of ER stress. In other systems, failure to mount the UPR results in increased cell death. As other studies have shown evidence for ER stress after brain ischemia and reperfusion, the failure of the UPR may play a significant role in reperfusion neuronal death.

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