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

• Published in: International journal of nanomedicine Vol. 15; pp. 7397 - 7413
• Main Authors: Liu, Ya-Qin, Xue, Si-Meng, Zhang, Peng, Xu, Lin-Na, Wang, De-Ping, Li, Guang, Cao, Ji-Min
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01.01.2020; Dove; Dove Medical Press
• Subjects: Action Potentials - drug effects; Animals; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - mortality; Cardiac arrhythmia; cardiac electrophysiology; Cardiomyocytes; Cells, Cultured; Electrocardiography; Embryos; Endocytosis - drug effects; Experiments; Glucose; Heart; ion channel; Ion Channels - metabolism; L-Lactate Dehydrogenase - metabolism; Laboratory animals; Male; Medical research; Membrane Potentials - drug effects; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nanomaterials; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - toxicity; nanotoxicology; Original Research; Patch-Clamp Techniques; Reactive Oxygen Species - metabolism; silica nanoparticle; Silicon Dioxide - toxicity; transmembrane potential; United States > US; cardiac electrophysiology; silica nanoparticle; ion channel; nanotoxicology; transmembrane potential
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S261692

The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated. 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. Within 30 min, both SiNPs (10 -10 g/mL) did not affect the resting potential and I channels. SiNP-100 increased the action potential amplitude (APA) and the I current density, but SiNP-20 decreased APA and I density. SiNP-100 prolonged the action potential duration (APD) and decreased the I current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased I density. Both SiNPs (10 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. SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the I and I channels and Ca homeostasis but not I 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.