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Int. J. Mol. Sci. 2018, 19(2), 419; https://doi.org/10.3390/ijms19020419

HDAC Inhibition Improves the Sarcoendoplasmic Reticulum Ca2+-ATPase Activity in Cardiac Myocytes

1
Institute for Biomedicine, Eurac Research, 39100 Bolzano, Italy (affiliated institute of the University of Lübeck, 23562 Lübeck, Germany)
2
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy
3
Department of Comparative Biomedicine and Food Science, University of Padova, 35020 Legnaro (Padova), Italy
4
Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino, IRCCS, 20138 Milano, Italy
5
Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, 20122 Milano, Italy
These authors contributed equally to this work.
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 14 December 2017 / Revised: 23 January 2018 / Accepted: 29 January 2018 / Published: 31 January 2018
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases)
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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. View Full-Text
Keywords: SERCA2; acetylation; HDAC inhibition; ATPase activity; calcium transients; cardiomyocyte mechanics SERCA2; acetylation; HDAC inhibition; ATPase activity; calcium transients; cardiomyocyte mechanics
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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. HDAC Inhibition Improves the Sarcoendoplasmic Reticulum Ca2+-ATPase Activity in Cardiac Myocytes. Int. J. Mol. Sci. 2018, 19, 419.

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