Editorial

3 pages, 184 KiB

Open AccessEditorial

The Role of Proteostasis Derailment in Cardiac Diseases

by Bianca J. J. M. Brundel

Cells 2020, 9(10), 2317; https://doi.org/10.3390/cells9102317 - 19 Oct 2020

Cited by 4 | Viewed by 2272

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing and changes in lifestyle. Prevailing theories about the mechanisms of cardiac disease onset feature the gradual derailment of cellular protein [...] Read more.

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing and changes in lifestyle. Prevailing theories about the mechanisms of cardiac disease onset feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of the protein quality control as central factors. In the heart, loss of protein patency, due to flaws in design (genetically) or environmentally-induced wear and tear, may overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac disease onset. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

Research

Jump to: Editorial, Review

15 pages, 2324 KiB

Open AccessArticle

Daily Supplementation of L-Glutamine in Atrial Fibrillation Patients: The Effect on Heat Shock Proteins and Metabolites

by Roeliene Starreveld, Kennedy S. Ramos, Agnes J. Q. M. Muskens, Bianca J. J. M. Brundel and Natasja M. S. de Groot

Cells 2020, 9(7), 1729; https://doi.org/10.3390/cells9071729 - 20 Jul 2020

Cited by 11 | Viewed by 4350

Abstract

Pharmaco-therapeutic strategies of atrial fibrillation (AF) are moderately effective and do not prevent AF onset and progression. Therefore, there is an urgent need to develop novel therapies. Previous studies revealed heat shock protein (HSP)-inducing compounds to mitigate AF onset and progression. Such an [...] Read more.

Pharmaco-therapeutic strategies of atrial fibrillation (AF) are moderately effective and do not prevent AF onset and progression. Therefore, there is an urgent need to develop novel therapies. Previous studies revealed heat shock protein (HSP)-inducing compounds to mitigate AF onset and progression. Such an HSP inducing compound is L-glutamine. In the current study we investigate the effect of L-glutamine supplementation on serum HSP27 and HSP70 levels and metabolite levels in patients with AF patients (n = 21). Hereto, HSP27 and HSP70 levels were determined by ELISAs and metabolites with LC-mass spectrometry. HSP27 levels significantly decreased after 3-months of L-glutamine supplementation [540.39 (250.97–1315.63) to 380.69 (185.68–915.03), p = 0.004] and normalized to baseline levels after 6-months of L-glutamine supplementation [634.96 (139.57–3103.61), p < 0.001]. For HSP70, levels decreased after 3-months of L-glutamine supplementation [548.86 (31.50–1564.51) to 353.65 (110.58–752.50), p = 0.045] and remained low after 6-months of L-glutamine supplementation [309.30 (118.29–1744.19), p = 0.517]. Patients with high HSP27 levels at baseline showed normalization of several metabolites related to the carbohydrates, nucleotides, amino acids, vitamins and cofactors metabolic pathways after 3-months L-glutamine supplementation. In conclusion, L-glutamine supplementation reduces the serum levels of HSP27 and HSP70 within 3-months and normalizes metabolite levels. This knowledge may fuel future clinical studies on L-glutamine to improve cardioprotective effects that may attenuate AF episodes. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

16 pages, 2291 KiB

Open AccessArticle

Cell-Free Circulating Mitochondrial DNA: A Potential Blood-Based Marker for Atrial Fibrillation

by Marit Wiersma, Denise M.S. van Marion, Emma J. Bouman, Jin Li, Deli Zhang, Kennedy S. Ramos, Eva A.H. Lanters, Natasja M.S. de Groot and Bianca J.J.M. Brundel

Cells 2020, 9(5), 1159; https://doi.org/10.3390/cells9051159 - 08 May 2020

Cited by 28 | Viewed by 4197

Abstract

Atrial fibrillation (AF), the most common, progressive tachyarrhythmia is associated with serious complications, such as stroke and heart failure. Early recognition of AF, essential to prevent disease progression and therapy failure, is hampered by the lack of accurate diagnostic serum biomarkers to identify [...] Read more.

Atrial fibrillation (AF), the most common, progressive tachyarrhythmia is associated with serious complications, such as stroke and heart failure. Early recognition of AF, essential to prevent disease progression and therapy failure, is hampered by the lack of accurate diagnostic serum biomarkers to identify the AF stage. As we previously showed mitochondrial dysfunction to drive experimental and human AF, we evaluated whether cell-free circulating mitochondrial DNA (cfc-mtDNA) represents a potential serum marker. Therefore, the levels of two mtDNA genes, COX3 and ND1, were measured in 84 control patients (C), 59 patients undergoing cardiac surgery without a history of AF (SR), 100 paroxysmal (PAF), 116 persistent (PeAF), and 20 longstanding-persistent (LS-PeAF) AF patients undergoing either cardiac surgery or AF treatment (electrical cardioversion or pulmonary vein isolation). Cfc-mtDNA levels were significantly increased in PAF patients undergoing AF treatment, especially in males and patients with AF recurrence after AF treatment. In PeAF and LS-PeAF, cfc-mtDNA levels gradually decreased. Importantly, cfc-mtDNA in serum may originate from cardiomyocytes, as in vitro tachypaced cardiomyocytes release mtDNA in the medium. The findings suggest that cfc-mtDNA is associated with AF stage, especially in males, and with patients at risk for AF recurrence after treatment. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Graphical abstract

20 pages, 6463 KiB

Open AccessArticle

ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage

by Hannah Louise Neumaier, Shelly Harel, Karin Klingel, Ziya Kaya, Arnd Heuser, Meike Kespohl and Antje Beling

Cells 2020, 9(5), 1093; https://doi.org/10.3390/cells9051093 - 28 Apr 2020

Cited by 7 | Viewed by 3616

Abstract

Inhibition of proteasome function by small molecules is highly efficacious in cancer treatment. Other than non-selective proteasome inhibitors, immunoproteasome-specific inhibitors allow for specific targeting of the proteasome in immune cells and the profound anti-inflammatory potential of such compounds revealed implications for inflammatory scenarios. [...] Read more.

Inhibition of proteasome function by small molecules is highly efficacious in cancer treatment. Other than non-selective proteasome inhibitors, immunoproteasome-specific inhibitors allow for specific targeting of the proteasome in immune cells and the profound anti-inflammatory potential of such compounds revealed implications for inflammatory scenarios. For pathogen-triggered inflammation, however, the efficacy of immunoproteasome inhibitors is controversial. In this study, we investigated how ONX 0914, an immunoproteasome-selective inhibitor, influences CoxsackievirusB3 infection in NMRI mice, resulting in the development of acute and chronic myocarditis, which is accompanied by formation of the immunoproteasome in heart tissue. In groups in which ONX 0914 treatment was initiated once viral cytotoxicity had emerged in the heart, ONX 0914 had no anti-inflammatory effect in the acute or chronic stages. ONX 0914 treatment initiated prior to infection, however, increased viral cytotoxicity in cardiomyocytes, promoting infiltration of myeloid immune cells into the heart. At this stage, ONX 0914 completely inhibited the β5 subunit of the standard cardiac proteasome and less efficiently blocked its immunoproteasome counterpart LMP7. In conclusion, ONX 0914 unselectively perturbs cardiac proteasome function in viral myocarditis of NMRI mice, reduces the capacity of the host to control the viral burden and promotes cardiac inflammation. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

22 pages, 4098 KiB

Open AccessArticle

SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy

by Julie Pires Da Silva, Kevin Monceaux, Arnaud Guilbert, Mélanie Gressette, Jérôme Piquereau, Marta Novotova, Renée Ventura-Clapier, Anne Garnier and Christophe Lemaire

Cells 2020, 9(2), 426; https://doi.org/10.3390/cells9020426 - 12 Feb 2020

Cited by 40 | Viewed by 5700

Abstract

Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response [...] Read more.

Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response and promotes cardiomyocyte survival. Here, we investigated whether and how autophagy plays a role in SIRT1-afforded cardioprotection against ER stress. The results revealed that protective autophagy was initiated before cell death in response to tunicamycin (TN)-induced ER stress in cardiac cells. SIRT1 inhibition decreased ER stress-induced autophagy, whereas its activation enhanced autophagy. In response to TN- or isoproterenol-induced ER stress, mice deficient for SIRT1 exhibited suppressed autophagy along with exacerbated cardiac dysfunction. At the molecular level, we found that in response to ER stress (i) the extinction of eEF2 or its kinase eEF2K not only reduced autophagy but further activated cell death, (ii) inhibition of SIRT1 inhibited the phosphorylation of eEF2, (iii) eIF2α co-immunoprecipitated with eEF2K, and (iv) knockdown of eIF2α reduced the phosphorylation of eEF2. Our results indicate that in response to ER stress, SIRT1 activation promotes cardiomyocyte survival by enhancing autophagy at least through activation of the eEF2K/eEF2 pathway. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

21 pages, 1782 KiB

Open AccessFeature PaperArticle

Mitochondrial Dysfunction Underlies Cardiomyocyte Remodeling in Experimental and Clinical Atrial Fibrillation

by Marit Wiersma, Denise M.S. van Marion, Rob C.I. Wüst, Riekelt H. Houtkooper, Deli Zhang, Natasja M.S. de Groot, Robert H. Henning and Bianca J.J.M. Brundel

Cells 2019, 8(10), 1202; https://doi.org/10.3390/cells8101202 - 05 Oct 2019

Cited by 58 | Viewed by 6365

Abstract

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD⁺ depletion in AF, suggesting a role for [...] Read more.

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD⁺ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca²⁺-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca²⁺-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

28 pages, 2849 KiB

Open AccessArticle

Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy

by Larissa M. Dorsch, Maike Schuldt, Cristobal G. dos Remedios, Arend F. L. Schinkel, Peter L. de Jong, Michelle Michels, Diederik W. D. Kuster, Bianca J. J. M. Brundel and Jolanda van der Velden

Cells 2019, 8(7), 741; https://doi.org/10.3390/cells8070741 - 18 Jul 2019

Cited by 22 | Viewed by 6330

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with [...] Read more.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCM_SMP) and 14 sarcomere mutation-negative (HCM_SMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCM_SMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were (1) several key PQC players were more abundant in HCM compared to controls, (2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCM_SMP compared to controls, (3) α-tubulin and acetylated α-tubulin levels were higher in HCM compared to controls, especially in HCM_HI, (4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with α-tubulin, and (5) α-tubulin levels correlated with acetylated α-tubulin and HSPs. Overall, carrying a mutation affects PQC and α-tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and α-tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

17 pages, 5044 KiB

Open AccessReview

ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart

by Bianca A. Meyer and Shirin Doroudgar

Cells 2020, 9(9), 2066; https://doi.org/10.3390/cells9092066 - 10 Sep 2020

Cited by 25 | Viewed by 8089

Abstract

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion [...] Read more.

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca²⁺ levels, for instance, stimulates the secretion of Ca²⁺-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled “The Role of Proteostasis Derailment in Cardiac Diseases.” Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

23 pages, 1676 KiB

Open AccessReview

Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

by Rajeshwary Ghosh, Vishaka Vinod, J. David Symons and Sihem Boudina

Cells 2020, 9(4), 933; https://doi.org/10.3390/cells9040933 - 10 Apr 2020

Cited by 29 | Viewed by 5875

Abstract

Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating [...] Read more.

Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

20 pages, 4221 KiB

Open AccessReview

Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

by Erik A. Blackwood, Alina S. Bilal, Winston T. Stauffer, Adrian Arrieta and Christopher C. Glembotski

Cells 2020, 9(3), 602; https://doi.org/10.3390/cells9030602 - 03 Mar 2020

Cited by 9 | Viewed by 5001

Abstract

The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac [...] Read more.

The heart exhibits incredible plasticity in response to both environmental and genetic alterations that affect workload. Over the course of development, or in response to physiological or pathological stimuli, the heart responds to fluctuations in workload by hypertrophic growth primarily by individual cardiac myocytes growing in size. Cardiac hypertrophy is associated with an increase in protein synthesis, which must coordinate with protein folding and degradation to allow for homeostatic growth without affecting the functional integrity of cardiac myocytes (i.e., proteostasis). This increase in the protein folding demand in the growing cardiac myocyte activates the transcription factor, ATF6 (activating transcription factor 6α, an inducer of genes that restore proteostasis. Previously, ATF6 has been shown to induce ER-targeted proteins functioning primarily to enhance ER protein folding and degradation. More recent studies, however, have illuminated adaptive roles for ATF6 functioning outside of the ER by inducing non-canonical targets in a stimulus-specific manner. This unique ability of ATF6 to act as an initial adaptive responder has bolstered an enthusiasm for identifying small molecule activators of ATF6 and similar proteostasis-based therapeutics. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

13 pages, 1747 KiB

Open AccessReview

Is Desmin Propensity to Aggregate Part of its Protective Function?

by Sonia R. Singh, Hikmet Kadioglu, Krishna Patel, Lucie Carrier and Giulio Agnetti

Cells 2020, 9(2), 491; https://doi.org/10.3390/cells9020491 - 20 Feb 2020

Cited by 19 | Viewed by 6078

Abstract

Desmin is the major protein component of the intermediate filaments (IFs) cytoskeleton in muscle cells, including cardiac. The accumulation of cleaved and misfolded desmin is a cellular hallmark of heart failure (HF). These desmin alterations are reversed by therapy, suggesting a causal role [...] Read more.

Desmin is the major protein component of the intermediate filaments (IFs) cytoskeleton in muscle cells, including cardiac. The accumulation of cleaved and misfolded desmin is a cellular hallmark of heart failure (HF). These desmin alterations are reversed by therapy, suggesting a causal role for the IFs in the development of HF. Though IFs are known to play a role in the protection from stress, a mechanistic model of how that occurs is currently lacking. On the other hand, the heart is uniquely suited to study the function of the IFs, due to its inherent, cyclic contraction. That is, HF can be used as a model to address how IFs afford protection from mechanical, and possibly redox, stress. In this review we provide a brief summary of the current views on the function of the IFs, focusing on desmin. We also propose a new model according to which the propensity of desmin to aggregate may have been selected during evolution as a way to dissipate excessive mechanical and possibly redox stress. According to this model, though desmin misfolding may afford protection from acute injury, the sustained or excessive accumulation of desmin aggregates could impair proteostasis and contribute to disease. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

15 pages, 1086 KiB

Open AccessFeature PaperReview

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

by Jin Li, Deli Zhang, Bianca J. J. M. Brundel and Marit Wiersma

Cells 2019, 8(12), 1617; https://doi.org/10.3390/cells8121617 - 12 Dec 2019

Cited by 34 | Viewed by 4827

Abstract

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. [...] Read more.

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function. Full article

(This article belongs to the Special Issue The Role of Proteostasis Derailment in Cardiac Diseases)

► Show Figures

Figure 1

Journal Menu

Journal Browser

The Role of Proteostasis Derailment in Cardiac Diseases

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (12 papers)

Editorial

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI