Changes in cardiac Nav1.5 expression, function, and acetylation by pan-histone deacetylase inhibitors.

Abstract

Histone deacetylase (HDAC) inhibitors are small molecule anticancer therapeutics that exhibit limiting cardiotoxicities including QT interval prolongation and life-threatening cardiac arrhythmias. Because the molecular mechanisms for HDAC inhibitor-induced cardiotoxicity are poorly understood, we performed whole cell patch voltage-clamp experiments to measure cardiac sodium currents (INa) from wild-type neonatal mouse ventricular or human-induced pluripotent stem cell-derived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228). All three pan-HDAC inhibitors dose dependently decreased peak INa density and shifted the voltage activation curve 3- to 8-mV positive. Increases in late INa were not observed despite a moderate slowing of the inactivation rate at low activating potentials (<-40 mV). Scn5a mRNA levels were not significantly altered but NaV1.5 protein levels were significantly reduced. Immunoprecipitation with anti-NaV1.5 and Western blotting with anti-acetyl-lysine antibodies indicated that NaV1.5 acetylation is increased in vivo after HDAC inhibition. FK228 inhibited total cardiac HDAC activity with two apparent IC50s of 5 nM and 1.75 μM, consistent with previous findings with TSA and VOR. FK228 also decreased ventricular gap junction conductance (gj), again consistent with previous findings. We conclude that pan-HDAC inhibition reduces cardiac INa density and NaV1.5 protein levels without affecting late INa amplitude and, thus, probably does not contribute to the reported QT interval prolongation and arrhythmias associated with pan-HDAC inhibitor therapies. Conversely, reductions in gj may enhance the occurrence of triggered activity by limiting electrotonic inhibition and, combined with reduced INa, slow myocardial conduction and increase vulnerability to reentrant arrhythmias.

• Authors: Qin Xu, Dakshesh Patel, Xian Zhang, Richard D Veenstra
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 311 Issue 5 Pg. H1139-H1149 (11 01 2016) ISSN: 1522-1539 [Electronic] United States
• PMID: 27638876 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Depsipeptides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• NAV1.5 Voltage-Gated Sodium Channel
• SCN5A protein, human
• Scn5a protein, mouse
• trichostatin A
• Vorinostat
• romidepsin

Topics

• Animals
• Animals, Newborn
• Arrhythmias, Cardiac (chemically induced)
• Blotting, Western
• Depsipeptides (pharmacology)
• Gap Junctions (drug effects)
• Heart Ventricles (cytology)
• Histone Deacetylase Inhibitors (adverse effects, pharmacology)
• Humans
• Hydroxamic Acids (pharmacology)
• Immunoprecipitation
• Induced Pluripotent Stem Cells
• Long QT Syndrome (chemically induced)
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism)
• NAV1.5 Voltage-Gated Sodium Channel (drug effects, genetics, metabolism)
• Patch-Clamp Techniques
• Real-Time Polymerase Chain Reaction
• Vorinostat