Activation of histone deacetylase-6 induces contractile dysfunction through derailment of α-tubulin proteostasis in experimental and human atrial fibrillation

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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.

METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.

CONCLUSIONS: AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.

Original languageEnglish
Pages (from-to)346-58
Number of pages13
JournalCirculation
Volume129
Issue number3
DOIs
Publication statusPublished - 21 Jan 2014

Cite this

Zhang, Deli ; Wu, Chia-Tung ; Qi, XiaoYan ; Meijering, Roelien A M ; Hoogstra-Berends, Femke ; Tadevosyan, Artavazd ; Cubukcuoglu Deniz, Gunseli ; Durdu, Serkan ; Akar, Ahmet Ruchan ; Sibon, Ody C M ; Nattel, Stanley ; Henning, Robert H ; Brundel, Bianca J J M. / Activation of histone deacetylase-6 induces contractile dysfunction through derailment of α-tubulin proteostasis in experimental and human atrial fibrillation. In: Circulation. 2014 ; Vol. 129, No. 3. pp. 346-58.
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title = "Activation of histone deacetylase-6 induces contractile dysfunction through derailment of α-tubulin proteostasis in experimental and human atrial fibrillation",
abstract = "BACKGROUND: Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.CONCLUSIONS: AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.",
keywords = "Acetylation, Animals, Atrial Fibrillation/metabolism, Atrial Remodeling/physiology, Calpain/metabolism, Cardiac Pacing, Artificial, Dogs, Drosophila, Drosophila Proteins/antagonists & inhibitors, HeLa Cells, Histone Deacetylase 6, Histone Deacetylases/metabolism, Humans, Hydroxamic Acids/pharmacology, Indoles/pharmacology, Mice, Microtubules/metabolism, Myocardial Contraction/physiology, Myocytes, Cardiac/cytology, Tubulin/metabolism",
author = "Deli Zhang and Chia-Tung Wu and XiaoYan Qi and Meijering, {Roelien A M} and Femke Hoogstra-Berends and Artavazd Tadevosyan and {Cubukcuoglu Deniz}, Gunseli and Serkan Durdu and Akar, {Ahmet Ruchan} and Sibon, {Ody C M} and Stanley Nattel and Henning, {Robert H} and Brundel, {Bianca J J M}",
year = "2014",
month = "1",
day = "21",
doi = "10.1161/CIRCULATIONAHA.113.005300",
language = "English",
volume = "129",
pages = "346--58",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
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Zhang, D, Wu, C-T, Qi, X, Meijering, RAM, Hoogstra-Berends, F, Tadevosyan, A, Cubukcuoglu Deniz, G, Durdu, S, Akar, AR, Sibon, OCM, Nattel, S, Henning, RH & Brundel, BJJM 2014, 'Activation of histone deacetylase-6 induces contractile dysfunction through derailment of α-tubulin proteostasis in experimental and human atrial fibrillation' Circulation, vol. 129, no. 3, pp. 346-58. https://doi.org/10.1161/CIRCULATIONAHA.113.005300

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; Cubukcuoglu Deniz, Gunseli; Durdu, Serkan; Akar, Ahmet Ruchan; Sibon, Ody C M; Nattel, Stanley; Henning, Robert H; Brundel, Bianca J J M.

In: Circulation, Vol. 129, No. 3, 21.01.2014, p. 346-58.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Activation of histone deacetylase-6 induces contractile dysfunction through derailment of α-tubulin proteostasis in experimental and human atrial fibrillation

AU - Zhang, Deli

AU - Wu, Chia-Tung

AU - Qi, XiaoYan

AU - Meijering, Roelien A M

AU - Hoogstra-Berends, Femke

AU - Tadevosyan, Artavazd

AU - Cubukcuoglu Deniz, Gunseli

AU - Durdu, Serkan

AU - Akar, Ahmet Ruchan

AU - Sibon, Ody C M

AU - Nattel, Stanley

AU - Henning, Robert H

AU - Brundel, Bianca J J M

PY - 2014/1/21

Y1 - 2014/1/21

N2 - BACKGROUND: Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.CONCLUSIONS: AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.

AB - BACKGROUND: Atrial fibrillation (AF) is characterized by structural remodeling, contractile dysfunction, and AF progression. Histone deacetylases (HDACs) influence acetylation of both histones and cytosolic proteins, thereby mediating epigenetic regulation and influencing cell proteostasis. Because the exact function of HDACs in AF is unknown, we investigated their role in experimental and clinical AF models.METHODS AND RESULTS: Tachypacing of HL-1 atrial cardiomyocytes and Drosophila pupae hearts significantly impaired contractile function (amplitude of Ca(2+) transients and heart wall contractions). This dysfunction was prevented by inhibition of HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing induced specific activation of HDAC6, resulting in α-tubulin deacetylation, depolymerization, and degradation by calpain. Tachypacing-induced contractile dysfunction was completely rescued by dominant-negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity. Furthermore, in vivo treatment with the HDAC6 inhibitor tubastatin A protected atrial tachypaced dogs from electric remodeling (action potential duration shortening, L-type Ca(2+) current reduction, AF promotion) and cellular Ca(2+)-handling/contractile dysfunction (loss of Ca(2+) transient amplitude, sarcomere contractility). Finally, atrial tissue from patients with AF also showed a significant increase in HDAC6 activity and reduction in the expression of both acetylated and total α-tubulin.CONCLUSIONS: AF induces remodeling and loss of contractile function, at least in part through HDAC6 activation and subsequent derailment of α-tubulin proteostasis and disruption of the cardiomyocyte microtubule structure. In vivo inhibition of HDAC6 protects against AF-related atrial remodeling, disclosing the potential of HDAC6 as a therapeutic target in clinical AF.

KW - Acetylation

KW - Animals

KW - Atrial Fibrillation/metabolism

KW - Atrial Remodeling/physiology

KW - Calpain/metabolism

KW - Cardiac Pacing, Artificial

KW - Dogs

KW - Drosophila

KW - Drosophila Proteins/antagonists & inhibitors

KW - HeLa Cells

KW - Histone Deacetylase 6

KW - Histone Deacetylases/metabolism

KW - Humans

KW - Hydroxamic Acids/pharmacology

KW - Indoles/pharmacology

KW - Mice

KW - Microtubules/metabolism

KW - Myocardial Contraction/physiology

KW - Myocytes, Cardiac/cytology

KW - Tubulin/metabolism

U2 - 10.1161/CIRCULATIONAHA.113.005300

DO - 10.1161/CIRCULATIONAHA.113.005300

M3 - Article

VL - 129

SP - 346

EP - 358

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 3

ER -