scholarly journals Endoplasmic reticulum and the microRNA environment in the cardiovascular system

2019 ◽  
Vol 97 (6) ◽  
pp. 515-527 ◽  
Author(s):  
Jody Groenendyk ◽  
Xiao Fan ◽  
Zhenling Peng ◽  
Lukasz Kurgan ◽  
Marek Michalak
Keyword(s):  
Endoplasmic Reticulum ◽  
Cardiovascular System ◽  
Stress Responses ◽  
Cardiac Myocyte ◽  
Cellular Stress ◽  
Cardiac Cells ◽  
Stress Coping ◽  
Coping Responses ◽  
The Unfolded Protein Response ◽  
The Impact

Stress responses are important to human physiology and pathology, and the inability to adapt to cellular stress leads to cell death. To mitigate cellular stress and re-establish homeostasis, cells, including those in the cardiovascular system, activate stress coping response mechanisms. The endoplasmic reticulum, a component of the cellular reticular network in cardiac cells, mobilizes so-called endoplasmic reticulum stress coping responses, such as the unfolded protein response. MicroRNAs play an important part in the maintenance of cellular and tissue homeostasis, perform a central role in the biology of the cardiac myocyte, and are involved in pathological cardiac function and remodeling. In this paper, we review a link between endoplasmic reticulum homeostasis and microRNA with an emphasis on the impact on stress responses in the cardiovascular system.

scholarly journals Differential regulation of cellular stress responses by the endoplasmic reticulum-resident Selenoprotein S (Seps1) in proliferating myoblasts versus myotubes

2018 ◽  
Vol 6 (24) ◽  
pp. e13926 ◽  
Author(s):  
Alex B. Addinsall ◽  
Sheree D. Martin ◽  
Fiona Collier ◽  
Xavier A. Conlan ◽  
Victoria C. Foletta ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Cellular Stress ◽  
Differential Regulation ◽  
Selenoprotein S ◽  
Cellular Stress Responses

Emerging roles of endoplasmic reticulum-resident selenoproteins in the regulation of cellular stress responses and the implications for metabolic disease

2018 ◽  
Vol 475 (6) ◽  
pp. 1037-1057 ◽  
Author(s):  
Alex B. Addinsall ◽  
Craig R. Wright ◽  
Sof Andrikopoulos ◽  
Chris van der Poel ◽  
Nicole Stupka
Keyword(s):  
Metabolic Disease ◽  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Cellular Stress ◽  
Metabolic Stress ◽  
Metabolic Dysfunction ◽  
Iodothyronine Deiodinase ◽  
Inflammatory Stress ◽  
Cellular Stress Responses

Chronic metabolic stress leads to cellular dysfunction, characterized by excessive reactive oxygen species, endoplasmic reticulum (ER) stress and inflammation, which has been implicated in the pathogenesis of obesity, type 2 diabetes and cardiovascular disease. The ER is gaining recognition as a key organelle in integrating cellular stress responses. ER homeostasis is tightly regulated by a complex antioxidant system, which includes the seven ER-resident selenoproteins — 15 kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins S, N, K, M and T. Here, the findings from biochemical, cell-based and mouse studies investigating the function of ER-resident selenoproteins are reviewed. Human experimental and genetic studies are drawn upon to highlight the relevance of these selenoproteins to the pathogenesis of metabolic disease. ER-resident selenoproteins have discrete roles in the regulation of oxidative, ER and inflammatory stress responses, as well as intracellular calcium homeostasis. To date, only two of these ER-resident selenoproteins, selenoproteins S and N have been implicated in human disease. Nonetheless, the potential of all seven ER-resident selenoproteins to ameliorate metabolic dysfunction warrants further investigation.

scholarly journals Stressors and Stress Responses in Cystic Fibrosis

2018 ◽  
Vol 5 (1) ◽  
pp. 11-29 ◽  
Author(s):  
Zsuzsa Bebok ◽  
Lianwu Fu
Keyword(s):  
Cystic Fibrosis ◽  
Stress Response ◽  
Stress Responses ◽  
Genetic Disorder ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Bicarbonate Transport ◽  
Persistent Infections ◽  
Human Disorders ◽  
The Unfolded Protein Response

Abstract Cystic fibrosis (CF) is a life-shortening, genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The primary cause of CF is reduced CFTR-mediated chloride and bicarbonate transport, due to mutations in CFTR. However, inflammation and persistent infections influence clinical outcome. Cellular stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), referred to here as cellular stress response pathways (SRPs), contribute to the pathology of human disorders. Multiple studies have indicated activation of SRPs in CF tissues. We review our present understanding of how SRPs are activated in CF and their contribution to pathology. We conclude that reduced CFTR function in CF organs establishes a tissue environment in which internal or external insults activate SRPs. SRPs contribute to CF pathogenesis by reducing CFTR expression, enhancing inflammation with consequent tissue remodeling. Understanding the contribution of SRPs to CF pathogenesis is crucial even in the era of CFTR “modulators” that are designed to potentiate, correct or amplify CFTR function, since there is an urgent need for supportive treatments. Importantly, CF patients with established pathology could benefit from the targeted use of drugs that modulate SRPs to reduce the symptoms.

scholarly journals Understanding Key Mechanisms of Exercise-Induced Cardiac Protection to Mitigate Disease: Current Knowledge and Emerging Concepts

2018 ◽  
Vol 98 (1) ◽  
pp. 419-475 ◽  
Author(s):  
Bianca C. Bernardo ◽  
Jenny Y. Y. Ooi ◽  
Kate L. Weeks ◽  
Natalie L. Patterson ◽  
Julie R. McMullen
Keyword(s):  
Stress Responses ◽  
Molecular Mechanisms ◽  
Cardiac Myocyte ◽  
Current Knowledge ◽  
Depth Profiling ◽  
Ubiquitin Proteasome System ◽  
Cardiac Cells ◽  
Cell Organelle ◽  
Cardiac Protection ◽  
Exercise Induced

The benefits of exercise on the heart are well recognized, and clinical studies have demonstrated that exercise is an intervention that can improve cardiac function in heart failure patients. This has led to significant research into understanding the key mechanisms responsible for exercise-induced cardiac protection. Here, we summarize molecular mechanisms that regulate exercise-induced cardiac myocyte growth and proliferation. We discuss in detail the effects of exercise on other cardiac cells, organelles, and systems that have received less or little attention and require further investigation. This includes cardiac excitation and contraction, mitochondrial adaptations, cellular stress responses to promote survival (heat shock response, ubiquitin-proteasome system, autophagy-lysosomal system, endoplasmic reticulum unfolded protein response, DNA damage response), extracellular matrix, inflammatory response, and organ-to-organ crosstalk. We summarize therapeutic strategies targeting known regulators of exercise-induced protection and the challenges translating findings from bench to bedside. We conclude that technological advancements that allow for in-depth profiling of the genome, transcriptome, proteome and metabolome, combined with animal and human studies, provide new opportunities for comprehensively defining the signaling and regulatory aspects of cell/organelle functions that underpin the protective properties of exercise. This is likely to lead to the identification of novel biomarkers and therapeutic targets for heart disease.

scholarly journals The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily M. Nakada ◽  
Rui Sun ◽  
Utako Fujii ◽  
James G. Martin
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Lung Structure ◽  
Selective Translation ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

scholarly journals Effect of Combined Stressors on C. elegans Lifespan

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 667-667
Author(s):  
Bradford Hull ◽  
George Sutphin
Keyword(s):  
Heavy Metal ◽  
Stress Response ◽  
Stress Responses ◽  
Cellular Response ◽  
Multiple Stressors ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
C Elegans ◽  
Arsenic Copper ◽  
The Impact

Abstract Cellular stress is a fundamental component of age-associated disease. Cells experience many forms of stress (oxidative, heavy metal, etc.), and as we age the burden of stress and resulting damage increases while our cells’ ability to deal with the consequences becomes diminished due to dysregulation of cellular stress response pathways. By understanding how cells respond to stress we aim to slow age-associated deterioration and develop treatment targets for age-associated disease. The majority of past work has focused on understanding responses to individual stressors. In contrast, how pathology and stress responses differ in the presence of multiple stressors is relatively unknown; we investigate that here. We cultured worms on agar plates with different combinations of arsenic, copper, and DTT (which create oxidative/proteotoxic, heavy metal, and endoplasmic reticulum (ER) stress, respectively) at doses that result in 20% lifespan reduction individually and measured the effect on lifespan. We found that arsenic/copper and arsenic/DTT combinations created additive lifespan reductions while the copper/DTT combination created an antagonistic lifespan reduction when compared to controls (p<0.05). This antagonistic toxicity suggests an interaction either between the mechanisms of toxicity or the cellular response to copper and DTT. We are now evaluating the impact of copper and DTT individually and in combination on unfolded protein and heavy metal response pathways to understand the underlying mechanism of the interaction. Additionally, we are continuing to screen stressors to identify combinations that cause non-additive (synergistic or antagonistic) toxicity to build a comprehensive model of the genetic stress response network in C. elegans.

scholarly journals Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

2019 ◽  
Vol 71 (5) ◽  
pp. 1659-1667 ◽  
Author(s):  
Taiaba Afrin ◽  
Danish Diwan ◽  
Katrina Sahawneh ◽  
Karolina Pajerowska-Mukhtar
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Translational Control ◽  
Protein Quality ◽  
Unfolded Protein ◽  
Transcriptional Gene Regulation ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

A Complex Scenario and Underestimated Challenge: The Tumor Microenvironment, ER Stress, and Cancer Treatment

2018 ◽  
Vol 25 (21) ◽  
pp. 2465-2502 ◽  
Author(s):  
Oleg I. Chen ◽  
Yaroslav P. Bobak ◽  
Oleh V. Stasyk ◽  
Leoni A. Kunz-Schughart
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Tumor Hypoxia ◽  
Cancer Treatments ◽  
Comprehensive Overview ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Complex Scenario ◽  
The Impact

The paradoxical role of ER stress in malignant diseases is only just being unraveled and remains incompletely understood. A particular challenge is the complex interplay between spaciotemporal and locoregional microenvironmental constraints in solid tumors and stress responses upon treatment; thus, the potential for new combinatorial therapeutic options to foster the coincidence of ER stress-related deadly events is likely to be underestimated. Without claiming this review to be complete, we present a comprehensive overview of the signaling mechanisms associated with the unfolded protein response (UPR) and the molecular link to cell survival and death mechanisms. We (i) delineate the mechanistic scenario and outcome of the UPR; (ii) discuss the role of ER stress in cancer development and progression; (iii) highlight the impact of various environmental conditions and stress stimuli, such as nutrient limitation and tumor hypoxia, in this context; and (iv) attempt to shed some light on the putative link between DNA damage, irradiation, and ER stress to emphasize the potential of therapeutic targeting of ER stress pathways for combined cancer treatments.

scholarly journals Protective role of Gipie, a Girdin family protein, in endoplasmic reticulum stress responses in endothelial cells

2011 ◽  
Vol 22 (6) ◽  
pp. 736-747 ◽  
Author(s):  
Etsushi Matsushita ◽  
Naoya Asai ◽  
Atsushi Enomoto ◽  
Yoshiyuki Kawamoto ◽  
Takuya Kato ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Responses ◽  
Protective Role ◽  
Jnk Pathway ◽  
Interacting Protein ◽  
Family Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response

Continued exposure of endothelial cells to mechanical/shear stress elicits the unfolded protein response (UPR), which enhances intracellular homeostasis and protect cells against the accumulation of improperly folded proteins. Cells commit to apoptosis when subjected to continuous and high endoplasmic reticulum (ER) stress unless homeostasis is maintained. It is unknown how endothelial cells differentially regulate the UPR. Here we show that a novel Girdin family protein, Gipie (78 kDa glucose-regulated protein [GRP78]-interacting protein induced by ER stress), is expressed in endothelial cells, where it interacts with GRP78, a master regulator of the UPR. Gipie stabilizes the interaction between GRP78 and the ER stress sensor inositol-requiring protein 1 (IRE1) at the ER, leading to the attenuation of IRE1-induced c-Jun N-terminal kinase (JNK) activation. Gipie expression is induced upon ER stress and suppresses the IRE1-JNK pathway and ER stress-induced apoptosis. Furthermore we found that Gipie expression is up-regulated in the neointima of carotid arteries after balloon injury in a rat model that is known to result in the induction of the UPR. Thus our data indicate that Gipie/GRP78 interaction controls the IRE1-JNK signaling pathway. That interaction appears to protect endothelial cells against ER stress-induced apoptosis in pathological contexts such as atherosclerosis and vascular endothelial dysfunction.

scholarly journals p32 protein levels are integral to mitochondrial and endoplasmic reticulum morphology, cell metabolism and survival

2013 ◽  
Vol 453 (3) ◽  
pp. 381-391 ◽  
Author(s):  
MengJie Hu ◽  
Simon A. Crawford ◽  
Darren C. Henstridge ◽  
Ivan H. W. Ng ◽  
Esther J. H. Boey ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Responses ◽  
Binding Protein ◽  
Cell Metabolism ◽  
Mitochondrial Protein ◽  
Basal Respiration ◽  
Protein Levels ◽  
Stress Dependent ◽  
The Impact

p32 [also known as HABP1 (hyaluronan-binding protein 1), gC1qR (receptor for globular head domains complement 1q) or C1qbp (complement 1q-binding protein)] has been shown previously to have both mitochondrial and non-mitochondrial localization and functions. In the present study, we show for the first time that endogenous p32 protein is a mitochondrial protein in HeLa cells under control and stress conditions. In defining the impact of altering p32 levels in these cells, we demonstrate that the overexpression of p32 increased mitochondrial fibrils. Conversely, siRNA-mediated p32 knockdown enhanced mitochondrial fragmentation accompanied by a loss of detectable levels of the mitochondrial fusion mediator proteins Mfn (mitofusin) 1 and Mfn2. More detailed ultrastructure analysis by transmission electron microscopy revealed aberrant mitochondrial structures with less and/or fragmented cristae and reduced mitochondrial matrix density as well as more punctate ER (endoplasmic reticulum) with noticeable dissociation of their ribosomes. The analysis of mitochondrial bioenergetics showed significantly reduced capacities in basal respiration and oxidative ATP turnover following p32 depletion. Furthermore, siRNA-mediated p32 knockdown resulted in differential stress-dependent effects on cell death, with enhanced cell death observed in the presence of hyperosmotic stress or cisplatin treatment, but decreased cell death in the presence of arsenite. Taken together, our studies highlight the critical contributions of the p32 protein to the morphology of mitochondria and ER under normal cellular conditions, as well as important roles of the p32 protein in cellular metabolism and various stress responses.

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