A paradox: Fe2+-containing agents decreased ROS and apoptosis induced by CoNPs in vascular endothelial cells by inhibiting HIF-1α.

Abstract

Cobalt nanoparticles (CoNPs) released from hip joint implants are known to have a toxic effect on several organs probably through increasing reactive oxygen species (ROS). Ferrous ion (Fe2+) is well-known to enhance oxidative stress by catalysing the production of ROS. However, in our pilot study, we found that Fe2+ conversely inhibited the ROS production induced by CoNPs. To elucidate the underlying mechanism, the present study treated vascular endothelial HUVEC and HMEC-1 cells with CoNPs alone or in combination with ferrous lactate [Fe(CH3CHOHCOO)2], ferrous succinate [Fe(CH2COO)2], and ferrous chloride (FeCl2). CoNP toxicity was evaluated by measuring cell viability, rate of apoptosis and lactose dehydrogenase (LDH) release, and intracellular ROS levels. Treatment with CoNPs decreased cell viability, LDH release, and ROS production and increased apoptosis. CoNPs increased hypoxia-inducible factor-1α (HIF-1α) protein level and mRNA levels of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT1) downstream of HIF-1α signalling. Silencing HIF-1α attenuated CoNP toxicity, as seen by recovery of cell viability, LDH release, and ROS levels and reduced apoptosis. CoNPs caused a pronounced reduction of Fe2+ in cells, but supplementation with Fe(CH3CHOHCOO)2, Fe(CH2COO)2, and FeCl2 restored Fe2+ levels and inhibited HIF-1α activation. Moreover, all three Fe2+-containing agents conferred protection from CoNPs; Fe(CH3CHOHCOO)2 and Fe(CH2COO)2 more effectively than FeCl2. In summary, the present study revealed that CoNPs exert their toxicity on human vascular endothelial cells by depleting intracellular Fe2+ level, which causes activation of HIF-1α signalling. Supplements of Fe2+, especially in the form of Fe(CH3CHOHCOO)2 and Fe(CH2COO)2, mitigated CoNP toxicity.

• Authors: Wenfeng Zhu, Yake Liu, Wei Wang, Zihua Zhou, Jin-Hua Gu, Zexu Zhang, Huanjian Sun, Fan Liu
• Journal: Bioscience reports (Biosci Rep) Vol. 41 Issue 1 (01 29 2021) ISSN: 1573-4935 [Electronic] England
• PMID: 33345265 (Publication Type: Journal Article)
• Copyright: © 2021 The Author(s).

Chemical References

• Ferrous Compounds
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Reactive Oxygen Species
• Cobalt

Topics

• Apoptosis (drug effects)
• Cobalt (chemistry)
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Ferrous Compounds (chemistry, metabolism, pharmacology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Metal Nanoparticles (chemistry, toxicity)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)