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

Abstract

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 [phone]Fax [phone]Email [email protected] 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 [phone]Fax [phone]Email [email protected]: 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

Keywords

• silica nanoparticle
• cardiac electrophysiology
• transmembrane potential
• ion channel
• nanotoxicology