Silica nanoparticles induce cardiac injury and dysfunction via ROS/Ca²⁺/CaMKII signaling

Interest is growing to better comprehend the interaction of silica nanoparticles (SiNPs) with the cardiovascular system. In particular, the extremely small size, relatively large surface area and associated unique properties may greatly enhance its toxic potentials compared to larger-sized counterparts. Nevertheless, the underlying mechanisms still need to be evaluated. In this context, the cardiotoxicity of nano-scale (Si-60; particle diameter about 60 nm) and submicro-scale silica particles (Si-300; 300 nm) were examined in ApoE^-/- mice via intratracheal instillation, 6.0 mg/kg·bw, once per week for 12 times. The echocardiography showed that the sub-chronic exposure of Si-60 declined cardiac output (CO) and stroke volume (SV), shorten LVIDd and LVIDs, and thickened LVAWs of ApoE^-/- mice in compared to the control and Si-300 groups. Histological investigations manifested Si-60 enhanced inflammatory infiltration, myocardial fiber arrangement disorder, hypertrophy and fibrosis in the cardiac tissue, as well as mitochondrial ultrastructural injury. Accordingly, the serum cTnT, cTnI and ANP were significantly elevated by Si-60, as well as cardiac ANP content. In particular, Si-60 greatly increased cardiac ROS, Ca²⁺ levels and CaMKII activation in comparison with Si-300. Further, in vitro investigations revealed silica particles induced a dose- and size-dependent activation of oxidative stress, mitochondrial membrane permeabilization, intracellular Ca²⁺ overload, CaMKII signaling activation and ensuing myocardial apoptosis in human cardiomyocytes (AC16). Mechanistic analyses revealed SiNPs induced myocardial apoptosis via ROS/Ca²⁺/CaMKII signaling, which may contribute to the abnormalities in cardiac structure and function in vivo. In summary, our research revealed SiNPs caused myocardial impairments, dysfunction and even structural remodeling via ROS/Ca²⁺/CaMKII signaling. Of note, a size-dependent myocardial toxicity was noticed, that is, Si-60 greater than Si-300.