TY  - JOUR
AB  - 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.
AU  - Freundt, Johanna K.
AU  - Frommeyer, Gerrit
AU  - Spieker, Georg Tilmann
AU  - Wötzel, Fabian
AU  - Schulze Grotthoff, Jochen
AU  - Stypmann, Jörg
AU  - Hempel, Georg
AU  - Schäfers, Michael
AU  - Jacobs, Andreas H.
AU  - Eckardt, Lars
AU  - Lange, Philipp Sebastian
DA  - 2019-03-06
DO  - https://doi.org/10.1186/s40360-019-0294-x
KW  - HDAC
KW  - Entinostat
KW  - Arrhythmias
KW  - Remodeling
KW  - Fibrosis
LA  - eng
N1  - BMC Pharmacology and Toxicology 20 (2019) 16, 1-9
N1  - Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster).
N1  - This work was supported by the fund “Innovative Medical Research” of the
University of Münster Medical School [I-LA11123].
PY  - 2019-03-06
TI  - Histone deacetylase inhibition by Entinostat for the prevention of electrical and structural remodeling in heart failure
UR  - https://nbn-resolving.org/urn:nbn:de:hbz:6-92109546463
Y2  - 2024-11-22T00:07:35
ER  -