Hdac inhibition improves the sarcoendoplasmic reticulum Ca2+-ATPase activity in cardiac myocytes

Viviana Meraviglia, Leonardo Bocchi, Roberta Sacchetto, Maria Cristina Florio, Benedetta M. Motta, Corrado Corti, Christian X. Weichenberger, Monia Savi, Yuri D’Elia, Marcelo D. Rosato-Siri, Silvia Suffredini, Chiara Piubelli, Giulio Pompilio, Peter P. Pramstaller, Francisco S. Domingues, Donatella Stilli, Alessandra Rossini

Research output: Contribution to journalArticle

Abstract

SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity. This was associated with a significant improvement of calcium transient recovery time and cell contractility. Previous reports have identified K464 as an acetylation site in human SERCA2. Mutants were generated where K464 was substituted with glutamine (Q) or arginine (R), mimicking constitutive acetylation or deacetylation, respectively. The K464Q mutation ameliorated ATPase activity and calcium transient recovery time, thus indicating that constitutive K464 acetylation has a positive impact on human SERCA2a (hSERCA2a) function. In conclusion, SAHA induced deacetylation inhibition had a positive impact on CM calcium handling, that, at least in part, was due to improved SERCA2 activity. This observation can provide the basis for the development of novel pharmacological approaches to ameliorate SERCA2 efficiency.

Original languageEnglish
Article number419
JournalInternational Journal of Molecular Sciences
Volume19
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

Keywords

  • Acetylation
  • ATPase activity
  • Calcium transients
  • Cardiomyocyte mechanics
  • HDAC inhibition
  • SERCA2

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Meraviglia, V., Bocchi, L., Sacchetto, R., Florio, M. C., Motta, B. M., Corti, C., Weichenberger, C. X., Savi, M., D’Elia, Y., Rosato-Siri, M. D., Suffredini, S., Piubelli, C., Pompilio, G., Pramstaller, P. P., Domingues, F. S., Stilli, D., & Rossini, A. (2018). Hdac inhibition improves the sarcoendoplasmic reticulum Ca2+-ATPase activity in cardiac myocytes. International Journal of Molecular Sciences, 19(2), [419]. https://doi.org/10.3390/ijms19020419