The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise

Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases.

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Stress in the kidney is the road to pERdition: is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy?

Journal of Endocrinology ◽

10.1530/joe-13-0517 ◽

2014 ◽

Vol 222 (3) ◽

pp. R97-R111 ◽

Cited By ~ 38

Author(s):

Aowen Zhuang ◽

Josephine M Forbes

Keyword(s):

Endoplasmic Reticulum ◽

Diabetic Nephropathy ◽

Er Stress ◽

Protein Turnover ◽

The Road ◽

Unfolded Protein ◽

Variable Nature ◽

Activating Transcription Factor ◽

The Unfolded Protein Response

The endoplasmic reticulum (ER) is an organelle that primarily functions to synthesise new proteins and degrade old proteins. Owing to the continual and variable nature of protein turnover, protein synthesis is inherently an error-prone process and is therefore tightly regulated. Fortunately, if this balance between synthesis and degradation is perturbed, an intrinsic response, the unfolded protein response (UPR) is activated to restore ER homoeostasis through the action of inositol-requiring protein 1, activating transcription factor 6 and PKR-like ER kinase transmembrane sensors. However, if the UPR is oversaturated and misfolded proteins accumulate, the ER can shift into a cytotoxic response, a physiological phenomenon known as ER stress. The mechanistic pathways of the UPR have been extensively explored; however, the role of this process in such a synthetic organ as the kidney requires further clarification. This review will focus on these aspects and will discuss the role of ER stress in specific resident kidney cells and how this may be integral in the pathogenesis and progression of diabetic nephropathy (DN). Given that diabetes is a perturbed state of protein turnover in most tissues, it is important to understand if ER stress is a secondary or tertiary response to other changes within the diabetic milieu or if it is an independent accelerator of kidney disease. Modulators of ER stress could provide a valuable tool for the treatment of DN and are under active investigation in other contexts.

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Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum

Biological Chemistry ◽

10.1515/hsz-2016-0108 ◽

2016 ◽

Vol 397 (7) ◽

pp. 649-656 ◽

Cited By ~ 10

Author(s):

Alexander R. van Vliet ◽

Abhishek D. Garg ◽

Patrizia Agostinis

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Signaling Pathways ◽

Unfolded Protein ◽

Independent Functions ◽

Intracellular Ca ◽

Stress Signals ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis

AbstractThe endoplasmic reticulum (ER) is the main coordinator of intracellular Ca2+signaling, protein synthesis, and folding. The ER is also implicated in the formation of contact sites with other organelles and structures, including mitochondria, plasma membrane (PM), and endosomes, thereby orchestrating through interorganelle signaling pathways, a variety of cellular responses including Ca2+homeostasis, metabolism, and cell death signaling. Upon loss of its folding capacity, incited by a number of stress signals including those elicited by various anticancer therapies, the unfolded protein response (UPR) is launched to restore ER homeostasis. The ER stress sensor protein kinase RNA-like ER kinase (PERK) is a key mediator of the UPR and its role during ER stress has been largely recognized. However, growing evidence suggests that PERK may govern signaling pathways through UPR-independent functions. Here, we discuss emerging noncanonical roles of PERK with particular relevance for the induction of danger or immunogenic signaling and interorganelle communication.

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Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice

Scientific Reports ◽

10.1038/s41598-020-76839-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yohei Kawaguchi ◽

Daisuke Hagiwara ◽

Takashi Miyata ◽

Yuichi Hodai ◽

Junki Kurimoto ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Arginine Vasopressin ◽

Urine Volume ◽

Neuronal Loss ◽

Protective Role ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Vasopressin Neurons

AbstractThe immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

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Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802254115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5203-E5212 ◽

Cited By ~ 19

Author(s):

Ya-Shiuan Lai ◽

Luciana Renna ◽

John Yarema ◽

Cristina Ruberti ◽

Sheng Yang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Er Stress ◽

Stress Responses ◽

Unfolded Protein ◽

Redox Activation ◽

Genetic Level ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

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Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under nonstress conditions

AJP Cell Physiology ◽

10.1152/ajpcell.00160.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. C992-C1003 ◽

Cited By ~ 39

Author(s):

Tracy Teodoro ◽

Tanya Odisho ◽

Elena Sidorova ◽

Allen Volchuk

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Survival ◽

Protein Levels ◽

Unfolded Protein ◽

Basal Expression ◽

Steady State Levels ◽

Activating Transcription Factor ◽

The Unfolded Protein Response ◽

Insulinoma Cells

Activating transcription factor 6 (ATF6) is one of three principle endoplasmic reticulum (ER) stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6α-p50, we found that active ATF6α was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6α-p50, we depleted endogenous ATF6α-p50 levels using small interfering RNA in insulinoma cells. Knockdown of endogenous ATF6α-p50 levels by ∼60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in nonstressed cells. Furthermore, ATF6α knockdown resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6α branch of the unfolded protein response (UPR) would result in ER stress. However, neither the PKR-like endoplasmic reticulum kinase (PERK), nor the inositol requiring enzyme 1 (IRE1) pathways of the UPR were significantly activated in ATF6α knockdown cells, although these cells were more sensitive to ER stress-inducing compounds. Interestingly, phosphorylation of JNK, p38, and c-Jun were elevated in ATF6α knockdown cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6α may have a role in maintaining β-cell survival even in the absence of ER stress.

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Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress–induced cell death during the unfolded protein response

Molecular Biology of the Cell ◽

10.1091/mbc.e13-11-0664 ◽

2014 ◽

Vol 25 (9) ◽

pp. 1411-1420 ◽

Cited By ~ 65

Author(s):

Nobuhiko Hiramatsu ◽

Carissa Messah ◽

Jaeseok Han ◽

Matthew M. LaVail ◽

Randal J. Kaufman ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Down Regulation ◽

Unfolded Protein ◽

Activity Loss ◽

The Unfolded Protein Response ◽

Protein Response

Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.

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Endoplasmic Reticulum Stress Signaling Pathways: Activation and Diseases

Current Protein and Peptide Science ◽

10.2174/1389203720666190621103145 ◽

2019 ◽

Vol 20 (9) ◽

pp. 935-943 ◽

Cited By ~ 6

Author(s):

Zhi Zheng ◽

Yuxi Shang ◽

Jiahui Tao ◽

Jun Zhang ◽

Bingdong Sha

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Misfolded Proteins ◽

Endogenous Factors ◽

Unfolded Protein ◽

Dependent Protein ◽

Activating Transcription Factor ◽

The Unfolded Protein Response ◽

Protein Response ◽

Sensor Molecules

Secretory and membrane proteins are folded in the endoplasmic reticulum (ER) prior to their exit. When ER function is disturbed by exogenous and endogenous factors, such as heat shock, ultraviolet radiation, hypoxia, or hypoglycemia, the misfolded proteins may accumulate, promoting ER stress. To rescue this unfavorable situation, the unfolded protein response is activated to reduce misfolded proteins within the ER. Upon ER stress, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6, are activated. Here, we discuss the mechanisms of PERK and IRE1 activation and describe two working models for ER stress initiation: the BiP-dependent model and the ligand-driven model. ER stress activation has been linked to multiple diseases, including cancers, Alzheimer’s disease, and diabetes. Thus, the regulation of ER stress may provide potential therapeutic targets for these diseases.

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Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

Endoplasmic Reticulum Stress in Diseases ◽

10.1515/ersc-2017-0004 ◽

2017 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Toru Hosoi ◽

Jun Nomura ◽

Keigo Tanaka ◽

Koichiro Ozawa ◽

Akinori Nishi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Neurodegenerative Diseases ◽

Er Stress ◽

Brain Function ◽

Review Article ◽

Double Stranded Rna ◽

Unfolded Protein ◽

Activating Transcription Factor ◽

The Unfolded Protein Response ◽

Protein Response

AbstractIncreasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.

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The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote resistance to endoplasmic reticulum stress

10.1101/457077 ◽

2018 ◽

Author(s):

Rolf M. Schmidt ◽

Sebastian Schuck

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Misfolded Proteins ◽

Secretory Proteins ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Multiple Signaling

ABSTRACTMisfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.

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Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9270107 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Shengjie Yang ◽

Min Wu ◽

Xiaoya Li ◽

Ran Zhao ◽

Yixi Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein ◽

Atherosclerotic Lesions ◽

Different Types ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis ◽

Progression Of Atherosclerosis

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

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