Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling

Abstract

Despite the widespread application of silica nanoparticles (SiNPs) in industrial, commercial, and biomedical fields, their response to human cells has not been fully elucidated. Overall, little is known about the toxicological effects of SiNPs on the cardiovascular system. In this study, SiNPs with a 58 nm diameter were used to study their interaction with human umbilical vein endothelial cells (HUVECs). Dose- and time-dependent decrease in cell viability and damage on cell plasma-membrane integrity showed the cytotoxic potential of the SiNPs. SiNPs were found to induce oxidative stress, as evidenced by the significant elevation of reactive oxygen species generation and malondialdehyde production and downregulated activity in glutathione peroxidase. SiNPs also stimulated release of cytoprotective nitric oxide (NO) and upregulated inducible nitric oxide synthase (NOS) messenger ribonucleic acid, while downregulating endothelial NOS and ET-1 messenger ribonucleic acid, suggesting that SiNPs disturbed the NO/NOS system. SiNP-induced oxidative stress and NO/NOS imbalance resulted in endothelial dysfunction. SiNPs induced inflammation characterized by the upregulation of key inflammatory mediators, including IL-1β, IL-6, IL-8, TNFα, ICAM-1, VCAM-1, and MCP-1. In addition, SiNPs triggered the activation of the Nrf2-mediated antioxidant system, as evidenced by the induction of nuclear factor-κB and MAPK pathway activation. Our findings demonstrated that SiNPs could induce oxidative stress, inflammation, and NO/NOS system imbalance, and eventually lead to endothelial dysfunction via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling. This study indicated a potential deleterious effect of SiNPs on the vascular endothelium, which warrants more careful assessment of SiNPs before their application.

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

“…8 Briefly, 2.5 mL of tetraethylorthosilicate was added to a premixed ethanol solution (50 mL) containing ammonia (2 mL) and water (1 mL). The reaction mixture was stirred (150 rpm) at 40°C for 12 hours.…”

“…The relative amount of redox-related factors, including Nrf2 and its downstream genes, such as SOD2, NQO1, TXN-1, and TXNRD-1, GCLC, and also hsp70 were quantified using real-time polymerase chain reaction according to our previous study. 8 All quantifications were performed with β-actin as an internal standard, and the relative amount of mRNA was calculated using the 2 -∆∆CT method.…”

“…6 Our previous studies showed that intratracheal-instilled SiNPs could pass through the alveolar-capillary barrier into systemic circulation, 7 and SiNPs triggered endothelial dysfunction. 8 However, knowledge on mechanisms of endothelial dysfunction is still limited. In our previous study, we found that SiNPs could increase ROS generation.…”

“…In our previous study, we found that SiNPs could increase ROS generation. 8 However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in SiNPsinduced endothelial injury have not been extensively studied. N-acetylcysteine (NAC) is known as an "antioxidant" in experimental models.…”

Interleukin-37: A crucial cytokine with multiple roles in disease and potentially clinical therapy (Review)

“…The mitogen activated protein kinases (MAPK) signal pathway is one of the main signaling pathways involved in immune responses, with vital roles in the regulation of cytokine and chemokine responses (32). There are three main components in the MAPK signaling pathway: The Jun N-terminal kinase (JNK 1/2/3), extracellular signal-regulated kinase (ERK1/2, ERK 3/4, ERK5, ERK 7/8,) and p38 MAPKs (p38α/β/γ/δ) (33)(34)(35)(36). Once stimulated, the MAPKs, which are expressed in all cell types, are activated and participate in various physiological and biologic processes including inflammation, growth, differentiation, survival and apoptosis of cells (35)(36)(37).…”