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

Choi, Seong-Woo; Yin, Ming-Zhe; Park, Na-Kyeong; Woo, Joo-Han; Kim, Sung-Joon

doi:10.3390/antiox10071139

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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

by

Seong-Woo Choi

¹,

Ming-Zhe Yin

^2,3,

Na-Kyeong Park

²,

Joo-Han Woo

¹ and

Sung-Joon Kim

^2,*

¹

Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Korea

²

Department of Physiology, Seoul National University College of Medicine, Seoul 03080, Korea

³

Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310058, China

^*

Author to whom correspondence should be addressed.

Antioxidants 2021, 10(7), 1139; https://doi.org/10.3390/antiox10071139

Submission received: 22 June 2021 / Revised: 13 July 2021 / Accepted: 15 July 2021 / Published: 19 July 2021

(This article belongs to the Special Issue Role of Oxidative Stress and Antioxidants in Pathophysiology: A Commemorative Special Issue in Honour of Professor Mario Umberto Dianzani)

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Abstract

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_V1.5 channel currents (I_NaV). Although the peak amplitude of I_NaV was not significantly changed by 4-ONE up to 10 μM, the rate of I_NaV inactivation was slowed, and the late Na⁺ current (I_NaL) became larger by 10 μM 4-ONE. The chemical modification of specific residues in hNa_V1.5 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 μM of 4-ONE was more prominent than that by 100 μM 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_V1.5.

Keywords: lipid peroxidation; 4-oxo-nonenal; heart; arrhythmia; late Na⁺ current

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MDPI and ACS Style

Choi, S.-W.; Yin, M.-Z.; Park, N.-K.; Woo, J.-H.; Kim, S.-J. 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. Antioxidants 2021, 10, 1139. https://doi.org/10.3390/antiox10071139

AMA Style

Choi S-W, Yin M-Z, Park N-K, Woo J-H, Kim S-J. 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. Antioxidants. 2021; 10(7):1139. https://doi.org/10.3390/antiox10071139

Chicago/Turabian Style

Choi, Seong-Woo, Ming-Zhe Yin, Na-Kyeong Park, Joo-Han Woo, and Sung-Joon Kim. 2021. "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" Antioxidants 10, no. 7: 1139. https://doi.org/10.3390/antiox10071139

APA Style

Choi, S.-W., Yin, M.-Z., Park, N.-K., Woo, J.-H., & Kim, S.-J. (2021). 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. Antioxidants, 10(7), 1139. https://doi.org/10.3390/antiox10071139

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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

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