Silica nanoparticles induce cardiotoxicity interfering with energetic status and Ca²⁺ handling in adult rat cardiomyocytes

Abstract

Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO₂) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO₂-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO₂ particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO₂ cell membrane association and internalization were analyzed. SiO₂ showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca²⁺ handling, which showed impaired contractility and intracellular Ca²⁺ transient amplitude during β-adrenergic stimulation in SiO₂ treatment. The time to 50% Ca²⁺ decay increased 39%, and the Ca²⁺ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) activity. Moreover, SiO₂ treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H₂O₂ generation were also observed. These data indicate that SiO₂ increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca²⁺ release, and reduced cell shortening. This mechanism of SiO₂ cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.<b>NEW & NOTEWORTHY</b> Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca²⁺ handling.