Dual Mechanisms of Cardiac Action Potential Prolongation by 4-Oxo-Nonenal Increasing the Risk of Arrhythmia; Late Na+ Current Induction and hERG K+ Channel Inhibition

4-Oxo-nonenal (4-ONE) is an endogenous lipid peroxidation product that is more reactive than 4-hydroxy-nonenal (4-HNE). We previously reported the arrhythmic potential of 4-HNE by suppression of cardiac human Ether-a-go-go Related Gene (hERG) K+ channels with prolonged action potential duration (APD) in cardiomyocytes. Here, we illustrate the higher arrhythmic risk of 4-ONE by modulating the cardiac hNa(V)1.5 channel currents (I-NaV). Although the peak amplitude of I-NaV was not significantly changed by 4-ONE up to 10 mu M, the rate of I-NaV inactivation was slowed, and the late Na+ current (I-NaL) became larger by 10 mu M 4-ONE. The chemical modification of specific residues in hNa(V)1.5 by 4-ONE was identified using MS-fingerprinting analysis. In addition to the changes in I-NaV, 4-ONE decreased the delayed rectifier K+ channel currents including the hERG current. The L-type Ca2+ channel current was decreased, whereas its inactivation was slowed by 4-ONE. The APD prolongation by 10 mu M of 4-ONE was more prominent than that by 100 mu M of 4-HNE. In the computational in silico cardiomyocyte simulation analysis, the changes of I-NaL by 4-ONE significantly exacerbated the risk of arrhythmia exhibited by the TdP marker, qNet. Our study suggests an arrhythmogenic effect of 4-ONE on cardiac ion channels, especially hNa(V)1.5.

Automated summary

4-ONE modulates cardiac ion channels, especially hNa(V)1.5, increasing the risk of arrhythmia.