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Int. J. Mol. Sci. 2018, 19(8), 2288; https://doi.org/10.3390/ijms19082288

Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart

1
Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY 13210, USA
2
Department of Cell and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Current Address: Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
*
Author to whom correspondence should be addressed.
Received: 15 July 2018 / Revised: 1 August 2018 / Accepted: 2 August 2018 / Published: 4 August 2018
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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Abstract

Class-selective histone deacetylase (HDAC) inhibitors were designed to improve safety profiles and therapeutic effectiveness in the treatment of multiple cancers relative to pan-HDAC inhibitors. However, the underlying mechanisms for their therapeutic and cardiotoxic potentials remain poorly understood. Cardiac sodium currents (INa) and gap junction conductance (gj) were measured by whole cell patch clamp techniques on primary cultures of neonatal cardiomyocytes. Cardiac NaV1.5 sodium channel and connexin43 (Cx43) gap junction protein levels were assessed by Western blot analyses. Panobinostat produced concentration-dependent reductions in ventricular gj, peak INa density, and NaV1.5 protein expression levels. Membrane voltage (Vm)-dependent activation of INa was shifted by +3 to 6 mV with no effect on inactivation. Entinostat (1 μM) did not affect ventricular gj, peak INa density, or INa activation. However, the INa half-inactivation voltage (V½) was shifted by −3.5 mV. Ricolinostat had only minor effects on ventricular gj and INa properties, though INa activation was shifted by −4 mV. Cx43 and NaV1.5 protein expression levels were not altered by class-selective HDAC inhibitors. The lack of effects of class-selective HDAC inhibitors on ventricular gj and INa may help explain the improved cardiac safety profile of entinostat and ricolinostat. View Full-Text
Keywords: histone deacetylase inhibitors; class-selective; gap junction; cardiac sodium channel; connexin43; NaV1.5; cardiotoxicity histone deacetylase inhibitors; class-selective; gap junction; cardiac sodium channel; connexin43; NaV1.5; cardiotoxicity
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Zhang, X.; Patel, D.; Xu, Q.; Veenstra, R. Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart. Int. J. Mol. Sci. 2018, 19, 2288.

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