학술논문
Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice
ORIGINAL RESEARCH
ORIGINAL RESEARCH
Document Type
Academic Journal
Source
International Journal of Nanomedicine. October 31, 2020, Vol. 15, p7397, 17 p.
Subject
Language
English
ISSN
1178-2013
Abstract
Introduction Silica (Si[O.sub.2]) nanoparticles (SiNPs) are becoming one of the most popular materials in many fields because of their unique physical and chemical properties. In the industrial field, SiNPs have [...]
Background: The toxicity of silica nanoparticles (SfNPs) on cardiac electrophysiology has seldom been evaluated. Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SfNP-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 SfNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SfNPs in vivo. SfNP endocytosis was observed using transmission electron microscopy. Results: Within 30 min, both SfNPs ([10.sup.-8]-[10.sup.-6] g/mL) did not affect the resting potential and IK1 channels. SfNP-100 increased the action potential amplitude (APA) and the INa current density, but SfNP-20 decreased APA and INa density. SfNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SfNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SfNPs ([10.sup.-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, SfNP-100 (4-10 mg/kg) and SfNP-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 SfNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice. Conclusion: SfNPs (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 [Ca.sup.2+] homeostasis but not IKi channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SfNP-100 is more toxic than SfNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo. Keywords: silica nanoparticle, cardiac electrophysiology, transmembrane potential, ion channel, nanotoxicology
Background: The toxicity of silica nanoparticles (SfNPs) on cardiac electrophysiology has seldom been evaluated. Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SfNP-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 SfNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SfNPs in vivo. SfNP endocytosis was observed using transmission electron microscopy. Results: Within 30 min, both SfNPs ([10.sup.-8]-[10.sup.-6] g/mL) did not affect the resting potential and IK1 channels. SfNP-100 increased the action potential amplitude (APA) and the INa current density, but SfNP-20 decreased APA and INa density. SfNP-100 prolonged the action potential duration (APD) and decreased the Ito current density, while SfNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased Ito density. Both SfNPs ([10.sup.-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, SfNP-100 (4-10 mg/kg) and SfNP-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 SfNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice. Conclusion: SfNPs (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 [Ca.sup.2+] homeostasis but not IKi channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SfNP-100 is more toxic than SfNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo. Keywords: silica nanoparticle, cardiac electrophysiology, transmembrane potential, ion channel, nanotoxicology