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 cellderived cardiomyocytes treated with trichostatin A (TSA), vorinostat (VOR), or romidepsin (FK228). All three pan-HDAC inhibitors dose dependently decreased peak INadensity and shifted the voltage activation curve 3-to 8-mV positive. Increases in late INawere not observed despite a moderate slowing of the inactivation rate at low activating potentials (