The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation
Open accessAbstract
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.
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Cites
HDAC6 is a microtubule-associated deacetylase
Hubbert, C., Guardiola, A., Shao, R., Kawaguchi, Y., Ito, A., Nixon, A., Yoshida, M., Wang, X.-F., & Yao, T.-P. (2002) · Nature · doi:10.1038/417455a · Cited by 2,403
HDAC family: What are the cancer relevant targets?
Witt, O., Deubzer, H. E., Milde, T., & Oehme, I. (2009) · Cancer Letters · doi:10.1016/j.canlet.2008.08.016 · Cited by 1,069
Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival
Yang, H., Yang, T., Baur, J. A., Perez, E., Matsui, T., Carmona, J. J., Lamming, D. W., Souza-Pinto, N. C., Bohr, V. A., Rosenzweig, A., et al. (2007) · Cell · doi:10.1016/j.cell.2007.07.035 · Cited by 950
Rational Design and Simple Chemistry Yield a Superior, Neuroprotective HDAC6 Inhibitor, Tubastatin A
Butler, K. V., Kalin, J., Brochier, C., Vistoli, G., Langley, B., & Kozikowski, A. P. (2010) · Journal of the American Chemical Society · doi:10.1021/ja102758v · Cited by 801
In vivo destabilization of dynamic microtubules by HDAC6‐mediated deacetylation
Matsuyama, A., Shimazu, T., Sumida, Y., Saito, A., Yoshimatsu, Y., Seigneurin‐Berny, D., Osada, H., Komatsu, Y., Nishino, N., Khochbin, S., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf682 · Cited by 720
HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin.
Iwata, A., Riley, B. E., Johnston, J. A., & Kopito, R. R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508786200 · Cited by 719
HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination
Boyault, C., Sadoul, K., Pabion, M., & Khochbin, S. (2007) · Oncogene · doi:10.1038/sj.onc.1210614 · Cited by 397 · cited 1×
“Furthermore, HDAC6 is the only cytosolic HDAC with 2 catalytic domains.(34) The second domain is responsible mainly for its TDAC activity.”
BackgroundHDAC6 is a target for protection and regeneration following injury in the nervous system
Rivieccio, M. A., Brochier, C., Willis, D. E., Walker, B. A., D'Annibale, M. A., McLaughlin, K., Siddiq, A., Kozikowski, A. P., Jaffrey, S. R., Twiss, J. L., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907935106 · Cited by 322
Cited by
Atrial Remodeling and Atrial Fibrillation
Nattel, S., & Harada, M. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.02.555 · Cited by 736
Self-citationBrundel, B. J. J. M., Ai, X., Hills, M. T., Kuipers, M. F., Lip, G. Y. H., & de Groot, N. M. S. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00347-9 · Cited by 499
Self-citationLysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease
Li, P., Ge, J., & Li, H. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0235-9 · Cited by 269
Proteostasis in cardiac health and disease
Henning, R. H., & Brundel, B. J. J. M. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.89 · Cited by 193
Self-citationDhiman, S., Mannan, A., Taneja, A., Mohan, M., & Singh, T. G. (2024) · Life Sciences · doi:10.1016/j.lfs.2024.122537 · Cited by 25
Metadata
- Authors
- Zhang, D., Wu, C.-T., Qi, X., Meijering, R. A. M., Hoogstra-Berends, F., Tadevosyan, A., Cubukcuoglu Deniz, G., Durdu, S., Akar, A. R., Sibon, O. C. M., Nattel, S., Henning, R. H., & Brundel, B. J. J. M.
- Venue
- Circulation
- Published
- 2014-01-21
- Volume
- 129
- Issue
- 3
- Pages
- 346-358
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2145162000
- Cited by
- 169
- References
- 8
- FWCI
- 7.63
- Type
- journal article
- Language
- en
- Open access
- green
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- Zhang, D., Wu, C.-T., Qi, X., Meijering, R. A. M., Hoogstra-Berends, F., Tadevosyan, A., Cubukcuoglu Deniz, G., Durdu, S., Akar, A. R., Sibon, O. C. M., Nattel, S., Henning, R. H., & Brundel, B. J. J. M. (2014). Activation of Histone Deacetylase-6 Induces Contractile Dysfunction Through Derailment of α-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation. Circulation. https://doi.org/10.1161/circulationaha.113.005300
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