Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice

Ya-Qin Liu1 *,* Si-Meng Xue1 *,* Peng Zhang1 *,* Lin-Na Xu,1 De-Ping Wang,2 Guang Li,1 Ji-Min Cao1,2 1Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovati...

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Autores principales:	Liu YQ, Xue SM, Zhang P, Xu LN, Wang DP, Li G, Cao JM
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	silica nanoparticle cardiac electrophysiology transmembrane potential ion channel nanotoxicology Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/735e20f14ff04768aa2189fa93976b75
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id	oai:doaj.org-article:735e20f14ff04768aa2189fa93976b75
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	silica nanoparticle cardiac electrophysiology transmembrane potential ion channel nanotoxicology Medicine (General) R5-920
spellingShingle	silica nanoparticle cardiac electrophysiology transmembrane potential ion channel nanotoxicology Medicine (General) R5-920 Liu YQ Xue SM Zhang P Xu LN Wang DP Li G Cao JM Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
description	Ya-Qin Liu1 , Si-Meng Xue1 , Peng Zhang1 , Lin-Na Xu,1 De-Ping Wang,2 Guang Li,1 Ji-Min Cao1,2 1Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 2Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China*These authors contributed equally to this work.Correspondence: Guang LiKey Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, 319 Zhongshan Road Section 3, Jiangyang District, Luzhou 646000, Sichuan Province, People’s Republic of ChinaTel +86 830-3161222Fax +86 830 3161222Email liguang@swmu.edu.cnJi-Min CaoKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, 56 Xin Jian Nan Lu Road, Taiyuan 030001, Shanxi Province, People’s Republic of ChinaTel +86 351 4235246Fax +86 351 4135117Email caojimin@126.comBackground: The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated.Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy.Results: Within 30 min, both SiNPs (10− 8– 10− 6 g/mL) did not affect the resting potential and IK1 channels. SiNP-100 increased the action potential amplitude (APA) and the INa current density, but SiNP-20 decreased APA and INa density. SiNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SiNPs (10− 6 g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4– 10 mg/kg) and SiNP-20 (4– 30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice.Conclusion: SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the INa and Ito channels and Ca2+ homeostasis but not IK1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.Keywords: silica nanoparticle, cardiac electrophysiology, transmembrane potential, ion channel, nanotoxicology
format	article
author	Liu YQ Xue SM Zhang P Xu LN Wang DP Li G Cao JM
author_facet	Liu YQ Xue SM Zhang P Xu LN Wang DP Li G Cao JM
author_sort	Liu YQ
title	Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
title_short	Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
title_full	Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
title_fullStr	Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
title_full_unstemmed	Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
title_sort	silica nanoparticles disturb ion channels and transmembrane potentials of cardiomyocytes and induce lethal arrhythmias in mice
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/735e20f14ff04768aa2189fa93976b75
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spelling	oai:doaj.org-article:735e20f14ff04768aa2189fa93976b752021-12-02T12:46:23ZSilica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice1178-2013https://doaj.org/article/735e20f14ff04768aa2189fa93976b752020-10-01T00:00:00Zhttps://www.dovepress.com/silica-nanoparticles-disturb-ion-channels-and-transmembrane-potentials-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Ya-Qin Liu1 , Si-Meng Xue1 , Peng Zhang1 , Lin-Na Xu,1 De-Ping Wang,2 Guang Li,1 Ji-Min Cao1,2 1Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 2Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, People’s Republic of China*These authors contributed equally to this work.Correspondence: Guang LiKey Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, 319 Zhongshan Road Section 3, Jiangyang District, Luzhou 646000, Sichuan Province, People’s Republic of ChinaTel +86 830-3161222Fax +86 830 3161222Email liguang@swmu.edu.cnJi-Min CaoKey Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Department of Physiology, Shanxi Medical University, 56 Xin Jian Nan Lu Road, Taiyuan 030001, Shanxi Province, People’s Republic of ChinaTel +86 351 4235246Fax +86 351 4135117Email caojimin@126.comBackground: The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated.Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy.Results: Within 30 min, both SiNPs (10− 8– 10− 6 g/mL) did not affect the resting potential and IK1 channels. SiNP-100 increased the action potential amplitude (APA) and the INa current density, but SiNP-20 decreased APA and INa density. SiNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SiNPs (10− 6 g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4– 10 mg/kg) and SiNP-20 (4– 30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice.Conclusion: SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the INa and Ito channels and Ca2+ homeostasis but not IK1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.Keywords: silica nanoparticle, cardiac electrophysiology, transmembrane potential, ion channel, nanotoxicologyLiu YQXue SMZhang PXu LNWang DPLi GCao JMDove Medical Pressarticlesilica nanoparticlecardiac electrophysiologytransmembrane potentialion channelnanotoxicologyMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 7397-7413 (2020)

Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice

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