A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy

Tetsuro Ago, Tong Liu, Peiyong Zhai, Wei Chen, Hong Li, Jeffery D. Molkentin, Stephen F. Vatner, Junichi Sadoshima

Research output: Contribution to journalArticle

219 Citations (Scopus)

Abstract

Thioredoxin 1 (Trx1) facilitates the reduction of signaling molecules and transcription factors by cysteine thiol-disulfide exchange, thereby regulating cell growth and death. Here we studied the molecular mechanism by which Trx1 attenuates cardiac hypertrophy. Trx1 upregulates DnaJb5, a heat shock protein 40, and forms a multiple-protein complex with DnaJb5 and class II histone deacetylases (HDACs), master negative regulators of cardiac hypertrophy. Both Cys-274/Cys-276 in DnaJb5 and Cys-667/Cys-669 in HDAC4 are oxidized and form intramolecular disulfide bonds in response to reactive oxygen species (ROS)-generating hypertrophic stimuli, such as phenylephrine, whereas they are reduced by Trx1. Whereas reduction of Cys-274/Cys-276 in DnaJb5 is essential for interaction between DnaJb5 and HDAC4, reduction of Cys-667/Cys-669 in HDAC4 inhibits its nuclear export, independently of its phosphorylation status. Our study reveals a novel regulatory mechanism of cardiac hypertrophy through which the nucleocytoplasmic shuttling of class II HDACs is modulated by their redox modification in a Trx1-sensitive manner.

Original languageEnglish
Pages (from-to)978-993
Number of pages16
JournalCell
Volume133
Issue number6
DOIs
Publication statusPublished - Jun 13 2008
Externally publishedYes

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Thioredoxins
Histone Deacetylases
Cardiomegaly
Oxidation-Reduction
Disulfides
HSP40 Heat-Shock Proteins
Phosphorylation
Cell Nucleus Active Transport
Cell growth
Phenylephrine
Cell death
Sulfhydryl Compounds
Cysteine
Reactive Oxygen Species
Cell Death
Transcription Factors
Up-Regulation
Molecules
Growth
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ago, T., Liu, T., Zhai, P., Chen, W., Li, H., Molkentin, J. D., ... Sadoshima, J. (2008). A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy. Cell, 133(6), 978-993. https://doi.org/10.1016/j.cell.2008.04.041

A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy. / Ago, Tetsuro; Liu, Tong; Zhai, Peiyong; Chen, Wei; Li, Hong; Molkentin, Jeffery D.; Vatner, Stephen F.; Sadoshima, Junichi.

In: Cell, Vol. 133, No. 6, 13.06.2008, p. 978-993.

Research output: Contribution to journalArticle

Ago, T, Liu, T, Zhai, P, Chen, W, Li, H, Molkentin, JD, Vatner, SF & Sadoshima, J 2008, 'A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy', Cell, vol. 133, no. 6, pp. 978-993. https://doi.org/10.1016/j.cell.2008.04.041
Ago, Tetsuro ; Liu, Tong ; Zhai, Peiyong ; Chen, Wei ; Li, Hong ; Molkentin, Jeffery D. ; Vatner, Stephen F. ; Sadoshima, Junichi. / A Redox-Dependent Pathway for Regulating Class II HDACs and Cardiac Hypertrophy. In: Cell. 2008 ; Vol. 133, No. 6. pp. 978-993.
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