Histone deacetylase inhibition by Entinostat for the prevention of electrical and structural remodeling in heart failure

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Abstract

Background

The development of heart failure is accompanied by complex changes in cardiac electrophysiology and functional properties of cardiomyocytes and fibroblasts. Histone deacetylase (HDAC) inhibitors hold great promise for the pharmaceutical therapy of several malignant diseases. Here, we describe novel effects of the class I HDAC inhibitor Entinostat on electrical and structural remodeling in an in vivo model of pacing induced heart failure.

Methods

Rabbits were implanted a pacemaker system, subjected to rapid ventricular pacing and treated with Entinostat or placebo, respectively. Following stimulation, rabbit hearts were explanted and subsequently subjected to electrophysiological studies and further immunohistological analyses of left ventricles.

Results

In vivo, rapid ventricular stimulation caused a significant prolongation of monophasic action potential duration compared to sham hearts (from 173 ± 26 ms to 250 ± 41 ms; cycle length 900 ms; p < 0.05) and an increased incidence of Early afterdepolarisations (+ 150%), while treatment with Entinostat in failing hearts could partially prevent this effect (from 250 ± 41 ms to 170 ± 53 ms, p < 0.05; reduction in EAD by 50%). Entinostat treatment partially restored KCNH2 and Cav1.3 gene expressions in failing hearts, and inhibited the development of cardiac fibrosis in vivo.

Conclusion

In a rabbit model of heart failure, Entinostat diminishes heart failure related prolongation of repolarization and partially restores KCNH2 and Cav1.3 expression. In addition, Entinostat exerts antifibrotic properties both in vitro and in vivo. Thus, Entinostat might be an interesting candidate for the pharmaceutical therapy of heart failure directed against structural and electrical remodeling.

Electronic supplementary material

The online version of this article (10.1186/s40360-019-0294-x) contains supplementary material, which is available to authorized users.

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Most cited references 24

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Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma.

Richard L. Piekarz, Robin Frye, Maria L.C. Turner … (2009)

PURPOSE Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. PATIENTS AND METHODS The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. CONCLUSION The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.

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Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy.

D Cao, R Delgado-Morales, Ying Y. Kong … (2011)

Histone deacetylases (HDACs) regulate cardiac plasticity; however, their molecular targets are unknown. As autophagy contributes to pathological cardiac remodeling, we hypothesized that HDAC inhibitors target autophagy. The prototypical HDAC inhibitor (HDACi), trichostatin A (TSA), attenuated both load- and agonist-induced hypertrophic growth and abolished the associated activation of autophagy. Phenylephrine (PE)-triggered hypertrophy and autophagy in cultured cardiomyocytes were each blocked by a panel of structurally distinct HDAC inhibitors. RNAi-mediated knockdown of either Atg5 or Beclin 1, two essential autophagy effectors, was similarly capable of suppressing ligand-induced autophagy and myocyte growth. RNAi experiments uncovered the class I isoforms HDAC1 and HDAC2 as required for the autophagic response. To test the functional requirement of autophagic activation, we studied mice that overexpress Beclin 1 in cardiomyocytes. In these animals with a fourfold amplified autophagic response to TAC, TSA abolished TAC-induced increases in autophagy and blunted load-induced hypertrophy. Finally, we subjected animals with preexisting hypertrophy to HDACi, finding that ventricular mass reverted to near-normal levels and ventricular function normalized completely. Together, these data implicate autophagy as an obligatory element in pathological cardiac remodeling and point to HDAC1/2 as required effectors. Also, these data reveal autophagy as a previously unknown target of HDAC inhibitor therapy.

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Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy.

Guangrong Lu, Kambeez Berenji, Eric Olson … (2006)

Recent work has demonstrated the importance of chromatin remodeling, especially histone acetylation, in the control of gene expression in the heart. In cell culture models of cardiac hypertrophy, pharmacological suppression of histone deacetylases (HDACs) can either blunt or amplify cell growth. Thus, HDAC inhibitors hold promise as potential therapeutic agents in hypertrophic heart disease. In the present investigation, we studied 2 broad-spectrum HDAC inhibitors in a physiologically relevant banding model of hypertrophy, observing dose-responsive suppression of ventricular growth that was well tolerated in terms of both clinical outcome and cardiac performance measures. In both short-term (3-week) and long-term (9-week) trials, cardiomyocyte growth was blocked by HDAC inhibition, with no evidence of cell death or apoptosis. Fibrotic change was diminished in hearts treated with HDAC inhibitors, and collagen synthesis in isolated cardiac fibroblasts was blocked. Preservation of systolic function in the setting of blunted hypertrophic growth was documented by echocardiography and by invasive pressure measurements. The hypertrophy-associated switch of adult and fetal isoforms of myosin heavy chain expression was attenuated, which likely contributed to the observed preservation of systolic function in HDAC inhibitor-treated hearts. Together, these data suggest that HDAC inhibition is a viable therapeutic strategy that holds promise in the treatment of load-induced heart disease.

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Author and article information

Contributors

Johanna K. Freundt: Johanna.Freundt@ukmuenster.de

Gerrit Frommeyer: Gerrit.Frommeyer@ukmuenster.de

Tilmann Spieker: spieker@pathologie-muenster.de

Fabian Wötzel: woetzel@pathologie-muenster.de

Jochen Schulze Grotthoff: jochenschulzeg@web.de

Jörg Stypmann: j.stypmann@asklepios.com

Georg Hempel: hempege@uni-muenster.de

Michael Schäfers: schafmi@uni-muenster.de

Andreas H. Jacobs: andreas.jacobs@johanniter-kliniken.de

Lars Eckardt: lars.eckardt@ukmuenster.de

Philipp S. Lange:

ORCID: http://orcid.org/0000-0002-7026-9609

+49 251/83-47820 , philippsebastian.lange@ukmuenster.de

Journal

Journal ID (nlm-ta): BMC Pharmacol Toxicol

Journal ID (iso-abbrev): BMC Pharmacol Toxicol

Title: BMC Pharmacology & Toxicology

Publisher: BioMed Central (London )

ISSN (Electronic): 2050-6511

Publication date (Electronic): 6 March 2019

Publication date PMC-release: 6 March 2019

Publication date Collection: 2019

Volume: 20

Electronic Location Identifier: 16

Affiliations

[1 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, Department of Cardiology II: Electrophysiology, , University Hospital Münster, ; Münster, Germany

[2 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, Department of Pathology, , University Hospital Münster, ; Münster, Germany

[3 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, Department of Cardiovascular Medicine, , University Hospital Münster, ; Münster, Germany

[4 ]ISNI 0000 0001 2172 9288, GRID grid.5949.1, Institute for Pharmaceutical and Medical Chemistry, , University of Münster, ; Münster, Germany

[5 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, European Institute for Molecular Imaging, , University Hospital Münster, ; Münster, Germany

[6 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, Department of Nuclear Medicine, , University Hospital Münster, ; Münster, Germany

Author information

Philipp S. Lange http://orcid.org/0000-0002-7026-9609

Article

Publisher ID: 294

DOI: 10.1186/s40360-019-0294-x

PMC ID: 6404297

PubMed ID: 30841920

SO-VID: 00eae391-dfdd-4999-8c29-7d3c0549caee

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 December 2017

Date accepted : 26 February 2019

Funding

Funded by: “Innovative Medical Research” of the University of Münster Medical School

Award ID: I-LA11123

Custom metadata

ScienceOpen disciplines: Toxicology

Keywords: hdac,entinostat,arrhythmias,remodeling,fibrosis

Data availability:

ScienceOpen disciplines: Toxicology

Keywords: hdac, entinostat, arrhythmias, remodeling, fibrosis

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Histone deacetylase inhibition by Entinostat for the prevention of electrical and structural remodeling in heart failure

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Abstract

Background

Methods

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Electronic supplementary material

Related collections

Journal of the Netherlands Society of Toxicology

Most cited references 24

Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma.

Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy.

Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy.

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Cited by 8

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