Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation

Zhang, Deli; Wu, Chia-Tung; Qi, Xiaoyan; Meijering, Roelien A. M.; Hoogstra-Berends, Femke; Tadevosyan, Artavazd; Deniz, Gunseli Cubukcuoglu; Durdu, Serkan; Akar, Achmet Ruchan; Sibon, Ody C. M.; Nattel, Stanley; Henning, Robert H.; Brundel, Bianca J. J. M.

doi:10.1161/circulationaha.113.005300

Cited by 133 publications

(181 citation statements)

References 42 publications

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“…Conservation of this network is of utmost importance to ensure proper PQC and cardiac function. Accordingly, attenuation of disruption of the cytoskeleton protects against cardiac diseases such as AF and heart failure (HF) [54][55][56] .…”

Section: Key Pointsmentioning

confidence: 99%

“…Several important components of proteostasis derailment have been identified, including depletion of chaperones, increased degrad ation via the protease calpain and ER stress induced autophagy, and post translational modifi cations of proteins. HDAC6 was identified to confer tachypacing induced post translational modifications of structural proteins, both in experimental models and clinical AF 55 . Rather than targeting histones, the increased HDAC6 activation specifically deacetylates α tubulin, resulting in the disintegration of the micro tubule network and subsequent degradation through calpain.…”

Section: Derailment Owing To Environmental Stressmentioning

confidence: 99%

“…Restoration of proteostasis is, therefore, likely to be beneficial in acquired cardiac diseases such as AF. Normalization of proteo stasis by preserving the cytoskeleton, through the induction of (small) HSPs or inhibition of HDAC6, might prevent derailment of proteostasis and, there fore, be an effective therapeutic approach to preserve cardiomyocyte function in AF 26,55 .…”

Section: Derailment Owing To Environmental Stressmentioning

confidence: 99%

“…Atrial fibrillation (AF) results in the downregulation of HSP gene expression 39 , so the first line of cell defence against stress is lost. In addition, AF induces the activation of histone deacetylase 6 (HDAC6), which results in de-acetylation of microtubules, alteration in calcium handling, and loss of contractile function 55 . Also, an endoplasmic reticulum (ER) stress response is observed with downstream activation of autophagy gene expression 27 .…”

Section: Conservation To Delay Cardiac Ageingmentioning

confidence: 99%

“…Also, an endoplasmic reticulum (ER) stress response is observed with downstream activation of autophagy gene expression 27 . Pharmacological treatments directed at induction of HSP transcription (with geranylgeranylacetone; GGA), prevention of ER stress (with 4-phenylbutyrate; 4PBA), and inhibition of HDAC6 activation (with tubastatin A) protect against proteostasis derailment and AF progression in tachypaced cardiomyocytes, Drosophila melanogaster, and dogs 26,55 . Ac, acetyl group; ATF, activating transcription factor; eIF2α, eukaryotic translation initiation factor 2α; HSPA5, heat-shock protein A5 (also known as 75 kDa glucose-regulated protein); IRE1, serine/threonine-protein kinase/endoribonuclease IRE1; PERK, eukaryotic translation initiation factor 2α-kinase 3; XBP1, X-box-binding protein 1. lifespan.…”

Section: Conservation To Delay Cardiac Ageingmentioning

confidence: 99%

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Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

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144

126

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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 ...

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Section: Key Pointsmentioning

confidence: 99%

Section: Derailment Owing To Environmental Stressmentioning

confidence: 99%

Section: Derailment Owing To Environmental Stressmentioning

confidence: 99%

Section: Conservation To Delay Cardiac Ageingmentioning

confidence: 99%

Section: Conservation To Delay Cardiac Ageingmentioning

confidence: 99%

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Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

Self Cite

144

126

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Histone deacetylase 6 as a novel promising target to treat cardiovascular disease

Wu,

Li,

et al. 2024

Cancer Innovation

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Histone deacetylase 6 (HDAC6) belongs to a class of epigenetic targets that have been found to be a key protein in the association between tumors and cardiovascular disease. Recent studies have focused on the crucial role of HDAC6 in regulating cardiovascular diseases such as atherosclerosis, myocardial infarction, myocardial hypertrophy, myocardial fibrosis, hypertension, pulmonary hypertension, and arrhythmia. Here, we review the association between HDAC6 and cardiovascular disease, the research progress of HDAC6 inhibitors in the treatment of cardiovascular disease, and discuss the feasibility of combining HDAC6 inhibitors with other therapeutic agents to treat cardiovascular disease.

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Atrial fibrillation fingerprinting; spotting bio‐electrical markers to early recognize atrial fibrillation by the use of a bottom‐up approach (AFFIP): Rationale and design

Starreveld

Knops

Ramos

et al. 2020

Clinical Cardiology

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BackgroundThe exact pathophysiology of atrial fibrillation (AF) remains incompletely understood and treatment of AF is associated with high recurrence rates. Persistence of AF is rooted in the presence of electropathology, defined as complex electrical conduction disorders caused by structural damage of atrial tissue. The atrial fibrillation fingerprinting (AFFIP) study aims to characterize electropathology, enabling development of a novel diagnostic instrument to predict AF onset and early progression.HypothesesHistory of AF, development of post‐operative AF, age, gender, underlying heart disease, and other clinical characteristics impact the degree of electropathology.MethodsThis study is a prospective observational study with a planned duration of 48 months. Three study groups are defined: (1) patients with (longstanding) persistent AF, (2) patients with paroxysmal AF, and (3) patients without a history of AF, all undergoing open‐chest cardiac surgery. Intra‐operative high‐resolution epicardial mapping is performed to identify the patient‐specific electrical profile, whereas the patient‐specific biological profile is assessed by evaluating proteostasis markers in blood samples and atrial appendage tissue samples. Post‐operative continuous rhythm monitoring is performed for detection of early post‐operative AF. Late post‐operative AF (during 5‐year follow‐up) is documented by either electrocardiogram or 24‐hour Holter registration.ResultsThe required sample size for this study is estimated at 447 patients. Up till now, 105 patients were included, of whom 36 have a history of AF.ConclusionThe AFFIP study will elucidate whether electrophysiological and structural characteristics represent a novel diagnostic tool, the AF fingerprint, to predict onset and early progression of AF in cardiac surgery patients.

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Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation

Cited by 133 publications

References 42 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Histone deacetylase 6 as a novel promising target to treat cardiovascular disease

Atrial fibrillation fingerprinting; spotting bio‐electrical markers to early recognize atrial fibrillation by the use of a bottom‐up approach (AFFIP): Rationale and design

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