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

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 (I) 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 I density and shifted the voltage activation curve 3- to 8-mV positive. Increases in late I 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 Na1.5 protein levels were significantly reduced. Immunoprecipitation with anti-Na1.5 and Western blotting with anti-acetyl-lysine antibodies indicated that Na1.5 acetylation is increased in vivo after HDAC inhibition. FK228 inhibited total cardiac HDAC activity with two apparent ICs of 5 nM and 1.75 μM, consistent with previous findings with TSA and VOR. FK228 also decreased ventricular gap junction conductance (g), again consistent with previous findings. We conclude that pan-HDAC inhibition reduces cardiac I density and Na1.5 protein levels without affecting late I amplitude and, thus, probably does not contribute to the reported QT interval prolongation and arrhythmias associated with pan-HDAC inhibitor therapies. Conversely, reductions in g may enhance the occurrence of triggered activity by limiting electrotonic inhibition and, combined with reduced I, slow myocardial conduction and increase vulnerability to reentrant arrhythmias.