Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy

Castillero, Estíbaliz; Akashi, Hirokazu; Pendrak, Klara; Yerebakan, Halit; Najjar, Marc; Wang, Catherine; Naka, Yoshifumi; Mancini, Donna; Sweeney, H. Lee; DʼArmiento, Jeanine; Ali, Ziad A.; Schulze, P. Christian; George, Isaac

doi:10.1152/ajpheart.00056.2015

Cited by 46 publications

(41 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, if UPR mechanisms are unable to lessen ER stress, cardiomyocyte apoptosis occurs which contributes to the development and maintenance of AF. 38 In addition, ER stress induced apoptosis is initiated via the activation of NF-κB. 34 .…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

Sirish

Timofeyev

et al. 2016

Circ: Arrhythmia and Electrophysiology

View full text Add to dashboard Cite

Background Atrial fibrillation (AF) represents the most common arrhythmia leading to increased morbidity and mortality, yet, current treatment strategies have proven inadequate. Conventional treatment with antiarrhythmic drugs carries a high risk for proarrhythmias. The soluble epoxide hydrolase enzyme (sEH) catalyzes the hydrolysis of anti-inflammatory epoxy fatty acids including epoxyeicosatrienoic acids (EETs) from arachidonic acid to the corresponding pro-inflammatory diols. Therefore, the goal of the study is to directly test the hypotheses that inhibition of the sEH enzyme can result in an increase in the levels of EETs leading to the attenuation of atrial structural and electrical remodeling and the prevention of AF. Methods and Results For the first time, we report findings that inhibition of sEH reduces inflammation, oxidative stress, atrial structural and electrical remodeling. Treatment with sEH inhibitor significantly reduces the activation of key inflammatory signaling molecules, including the transcription factor nuclear factor κ-light-chain-enhancer (NF-κB), mitogen-activated protein kinase (MAPK) and transforming growth factor-β (TGF-β). Conclusions This study provides insights into the underlying molecular mechanisms leading to AF by inflammation and represents a paradigm shift from conventional antiarrhythmic drugs which block downstream events to a novel upstream therapeutic target by counteracting the inflammatory processes in AF.

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

Sirish

Timofeyev

et al. 2016

Circ: Arrhythmia and Electrophysiology

View full text Add to dashboard Cite

show abstract

“…The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 .…”

mentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

138

126

View full text Add to dashboard Cite

The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

show abstract

“…Investigators took paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation (Castillero et al, ). Their study indicated that mechanical unloading by left ventricular assisted devices can improve cardiac markers of ER stress and cell death in advanced heart failure mediated by the improvement of calcium handling in patients with advanced heart failure.…”

Section: The Unfolded Protein Response Under Oxidative Stressmentioning

confidence: 99%

“…Apoptosis as reflected by CEBP homologous protein and DNA damage were also significantly reduced. Improved left ventricular dimensions positively correlated with P‐eIF2/eIF2 and apoptosis level of dysregulation of calcium‐handling proteins, including, P‐ryanodine receptor, Ca 2+ storing protein calsequestrin, Na‐Ca 2+ exchanger, sarcoendoplasmic reticulum Ca 2+ ‐ATPase (SERCA2a), ER chaperone protein calreticulin when function was normalized (Castillero et al, ).…”

Section: The Unfolded Protein Response Under Oxidative Stressmentioning

confidence: 99%

What role does the stress response have in congestive heart failure?

Badreddin

Youssef

Attia

et al. 2017

Journal Cellular Physiology

View full text Add to dashboard Cite

This review is concerned with cardiac malfunction as a result of an imbalance in protein proteostasis, the homeostatic balance between protein removal and regeneration in a long remodeling process involving the endoplasmic reticulum (ER) and the unfolded protein response (UPR). The importance of this is of special significance with regard to cardiac function as a high energy requiring muscular organ that has a high oxygen requirement and is highly dependent on mitochondria. The importance of mitochondria is not only concerned with high energy dependence on mitochondrial electron transport, but it also has a role in the signaling between the mitochondria and the ER under stress. Proteins made in the ER are folded as a result of sulfhydryl groups (-SH) and attractive and repulsive reactions in the tertiary structure. We discuss how this matters with respect to an imbalance between muscle breakdown and repair in a stressful environment, especially as a result of oxidative and nitrosative byproducts of mitochondrial activity. The normal repair is a remodeling, but under this circumstance, the cell undergoes or even lysosomal "self eating" autophagy, or even necrosis instead of apoptosis. We shall discuss the relationship of the UPR pathway to chronic congestive heart failure (CHF).

show abstract

Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy

Abstract: George I. Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy.

Cited by 46 publications

References 40 publications

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation

Proteostasis in cardiac health and disease

What role does the stress response have in congestive heart failure?

Contact Info

Product

Resources

About