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.

Exploring the Causal Effects of Mineral Metabolism Disorders on Telomere and Mitochondrial DNA: A Bidirectional Two-Sample Mendelian Randomization Analysis

“…Additionally, iron plays a crucial role in the activation of certain antioxidant enzymes, including superoxide dismutase (SOD), which aids in mitigating oxidative stress and safeguarding mtDNA integrity [81,82]. Nevertheless, the excessive accumulation of iron can result in detrimental consequences, including heightened oxidative stress that may compromise mitochondrial integrity and functionality, ultimately hastening cellular senescence [83][84][85]. Oxidative stress, characterized by the deleterious impact of reactive species such as free radicals on cellular components such as lipids, proteins, and DNA, can be exacerbated by iron due to its role as a potent reductant that catalyzes the generation of additional free radicals [86,87].…”

Transition metals in angiogenesis – A narrative review

“…As with various NPs, toxicity remains a topic of discussion, and researchers also underline the possible adverse effects of cobalt NPs [ 107 ]. Cobalt-chromium based materials, commonly used in hip implants due to favorable characteristics, have been shown to release small particles over time [ 108 ].…”

“…This damage is linked to oxidative stress from cobalt exposure. Indeed, cobalt can stimulate HIF1-α under normoxic conditions, which can result in adverse reactions including apoptosis [ 107 ]. Specifically, cobalt NPs display higher toxic effects than CoCl2 [ 110 ].…”

“…Specifically, cobalt NPs display higher toxic effects than CoCl2 [ 110 ]. Interestingly, the toxic effects of cobalt NPs in HUVECs could be reduced through Fe 2+ containing molecules, namely ferrous lactate [Fe(CH 3 CHOHCOO) 2 ] and ferrous succinate [Fe(CH 2 COO) 2 ] [ 107 ].…”

Fluorescent Carbon Dots for Sensitive and Rapid Monitoring of Intracellular Ferrous Ion

“…Few reported CDs have been designed for specific detection of divalent ferrous Fe 2+ ions over ferric ions [ 18 , 19 , 20 ] and successfully applied to monitor the intracellular Fe 2+ ions [ 16 , 21 ]. Ferrous ions enhance oxidative stress by catalyzing the production of reactive oxygen species that induce biochemical signaling processes, leading to degenerative diseases such as cancer, Alzheimer’s disease, and Parkinson’s disease [ 22 , 23 , 24 ]. Therefore, due to the distinctive properties of fluorescent CDs and the necessity of intracellular ferrous ion detection, it is highly desired to successfully explore the Fe 2+ -sensitive CDs for rapid determination of intracellular ferrous ions.…”