Differences in Functional Expression of Connexin43 and Na_V1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart

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 (I_Na) and gap junction conductance (g_j) were measured by whole cell patch clamp techniques on primary cultures of neonatal cardiomyocytes. Cardiac Na_V1.5 sodium channel and connexin43 (Cx43) gap junction protein levels were assessed by Western blot analyses. Panobinostat produced concentration-dependent reductions in ventricular g_j, peak I_Na density, and Na_V1.5 protein expression levels. Membrane voltage (V_m)-dependent activation of I_Na was shifted by +3 to 6 mV with no effect on inactivation. Entinostat (1 μM) did not affect ventricular g_j, peak I_Na density, or I_Na activation. However, the I_Na half-inactivation voltage (V_½) was shifted by −3.5 mV. Ricolinostat had only minor effects on ventricular g_j and I_Na properties, though I_Na activation was shifted by −4 mV. Cx43 and Na_V1.5 protein expression levels were not altered by class-selective HDAC inhibitors. The lack of effects of class-selective HDAC inhibitors on ventricular g_j and I_Na may help explain the improved cardiac safety profile of entinostat and ricolinostat. View Full-Text