Related Experiment Video
Updated: Feb 7, 2026
Expression Analysis of Mammalian Linker-histone Subtypes
Published on: March 19, 2012
Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase
Xian Zhang1, Dakshesh Patel2, Qin Xu3
1Department of Pharmacology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY 13210, USA. ZhangXi@upstate.edu.
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.
Insights
Class-selective histone deacetylase (HDAC) inhibitors show improved cardiac safety. Entinostat and ricolinostat minimally impacted cardiac sodium currents and gap junction conductance, unlike panobinostat.
Area of Science:
- Cardiovascular Pharmacology
- Cancer Therapeutics
- Molecular Cardiology
Background:
- Histone deacetylase (HDAC) inhibitors are investigated for cancer treatment, with class-selective agents aiming for better safety than pan-HDAC inhibitors.
- The mechanisms underlying the therapeutic and cardiotoxic effects of class-selective HDAC inhibitors are not fully understood.
- Cardiac electrophysiology, specifically sodium currents (INa) and gap junction conductance (gj), are critical for heart function and potential drug toxicity.
Purpose of the Study:
- To investigate the effects of class-selective HDAC inhibitors (entinostat, ricolinostat) and a pan-HDAC inhibitor (panobinostat) on cardiac electrophysiological properties and protein expression.
- To compare the cardiotoxic potential of class-selective HDAC inhibitors with panobinostat at the cellular level.
- To elucidate the impact of these inhibitors on NaV1.5 sodium channels and connexin43 (Cx43) gap junctions.
Main Methods:
- Whole-cell patch clamp electrophysiology was used to measure INa and gj in primary neonatal rat cardiomyocyte cultures.
- Western blot analysis was employed to quantify NaV1.5 and Cx43 protein expression levels.
- Concentration-dependent and specific dose (1 μM) effects of the inhibitors were assessed.
Main Results:
- Panobinostat caused concentration-dependent decreases in gj, peak INa density, and NaV1.5 protein, along with a positive shift in INa activation.
- Entinostat (1 μM) did not affect gj or peak INa density but caused a negative shift in INa inactivation (V½).
- Ricolinostat showed minor effects on gj and INa, with a negative shift in INa activation; neither entinostat nor ricolinostat altered NaV1.5 or Cx43 protein levels.
Conclusions:
- Class-selective HDAC inhibitors like entinostat and ricolinostat exhibit a more favorable cardiac electrophysiological profile compared to panobinostat.
- The minimal impact of entinostat and ricolinostat on ventricular gj and INa properties may contribute to their improved cardiac safety.
- These findings highlight the importance of evaluating drug-specific effects on cardiac ion channels and proteins to predict cardiotoxicity.
More Related Videos
09:07Single-Step Enrichment of a TAP-Tagged Histone Deacetylase of the Filamentous Fungus Aspergillus nidulans for Enzymatic Activity Assay
Published on: May 1, 2019
07:38Functional Characterization of Na+/H+ Exchangers of Intracellular Compartments Using Proton-killing Selection to Express Them at the Plasma Membrane
Published on: March 30, 2015
Related Concept Videos
02:32Histone Modification
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone...
02:32Histone Modification
02:30Histone Variants at the Centromere
00:46Feedback Inhibition
02:04Co-activators and Co-repressors
01:42What is Gene Expression?
Gene expression is the process in which DNA directs the synthesis of functional products, that is, proteins. Cells can regulate gene expression at various stages. It allows organisms to generate different cell types and enables cells to adapt to internal and external factors.
Genetic Information Flows from DNA to RNA to Protein
A gene is a stretch of DNA that serves as the blueprint for functional RNAs and proteins. Since DNA is made up of nucleotides and proteins consist of amino...