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

Abstract

Environmental exposure to silica nanoparticles (SiNPs) is inevitable due to their widespread application in industrial, commercial, and biomedical fields. In recent years, most investigators focus on the evaluation of cardiovascular effects of SiNPs in vivo and in vitro. Endothelial injury and dysfunction is now hypothesized to be a dominant mechanism in the development of cardiovascular diseases. This study aimed to explore interaction of SiNPs with endothelial cells, and extensively investigate the exact effects of reactive oxygen species (ROS) on the signaling molecules and cytotoxicity involved in SiNPs-induced endothelial injury. Significant induction of cytotoxicity as well as oxidative stress, apoptosis, and autophagy was observed in human umbilical vein endothelial cells following the SiNPs exposure ( P <0.05). The oxidative stress was induced by ROS generation, leading to redox imbalance and lipid peroxidation. SiNPs induced mitochondrial dysfunction, characterized by membrane potential collapse, and elevated Bax and declined bcl-2 expression, ultimately leading to apoptosis, and also increased number of autophagosomes and autophagy marker proteins, such as LC3 and p62. Phosphorylated ERK, PI3K, Akt, and mTOR were significantly decreased, but phosphorylated JNK and p38 MAPK were increased in SiNPs-exposed endothelial cells. In contrast, all of these stimulation phenomena were effectively inhibited by N -acetylcysteine. The N -acetylcysteine supplement attenuated SiNPs-induced endothelial toxicity through inhibition of apoptosis and autophagy via MAPK/Bcl-2 and PI3K/Akt/mTOR signaling, as well as suppression of intracellular ROS property via activating antioxidant enzyme and Nrf2 signaling. In summary, the results demonstrated that SiNPs triggered autophagy and apoptosis via ROS-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling in endothelial cells, and subsequently disturbed the endothelial homeostasis and impaired endothelium. Our findings may provide experimental evidence and explanation for cardiovascular diseases triggered by SiNPs. Furthermore, results hint that the application of antioxidant may provide a novel way for safer use of nanomaterials.

Apoptotic effects of hsian‐tsao (Mesona procumbens Hemsley) on hepatic stellate cells mediated by reactive oxygen species and ERK, JNK, and caspase‐3 pathways

“…N‐acetyl‐cysteine can prevent JNK phosphorylation in human gastric carcinoma MKN45 cells (Guo et al, ) and can reverse the overexpression of p38‐associated pathways in vascular endothelial cells (Bhattacharya, Halder, Mukhopadhyay, & Giri, ) and human melanoma cells (Bell et al, ). It has been reported that Pin was isolated from the gorgonian coral Pinnigorgia sp., which triggered the activated HSCs to undergo apoptosis via ROS‐ERK/JNK‐caspase‐3 signaling and probably caused the clearance of HSCs (Kuo et al, ).…”

“…N-acetyl-cysteine can prevent JNK phosphorylation in human gastric carcinoma MKN45 cells (Guo et al, 2016) and can reverse the overexpression of p38-associated pathways in vascular endothelial cells (Bhattacharya, Halder, Mukhopadhyay, & Giri, 2009) and human melanoma cells (Bell et al, 2010). It has been The experiments were independently repeated three times (n = 3).…”

Pathological study of pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): Effects of lowered serum zinc level on the toxicity

“…Activation of autophagy was demonstrated in the alveolar macrophages of silicosis mouse model [49] and in the cultured alveolar macrophages exposed to silica [50][51][52][53] in response to silicon toxicity; autophagy is an important pro-survival mechanism for maintaining metabolic homeostasis under stress [54, [56]. Positive immunolabeling for LC-3 (an marker of autophagy) and LAMP-1 www.fhc.viamedica.pl (a lysosome marker) was also observed in the cytoplasm of enlarged macrophages containing fine ASD particles; positive LC-3 staining was less prominent in low level serum Zn mice, suggesting that autophagy was being blocked as a result of Zn deficiency.…”

Polymeric Nanomicelles: A Potential Hazard for the Cardiovascular System?

“…Autophagy of VSMCs and endothelial cells can be triggered by inflammatory mediators, ROS, oxLDL, TNF-α and osteopontin. There is evidence indicating that NPs trigger the autophagy process in vascular endothelial cells [14], while it remains unknown whether PMs could regulate autophagy in cardiovascular cells.…”