Iron oxide nanoparticles cause surface coating- and core chemistry-dependent endothelial cell ferroptosis

Abstract

Iron oxide nanoparticles (IONPs) are mostly intended to be administrated intravenously, understanding the interaction of IONPs with vascular endothelial cells is extremely crucial for developing safe application regimes of IONPs. In this work, interactions of three kinds of IONPs to endothelial cells were investigated both in human umbilical vein endothelial cells (HUVECs) and in healthy mice. Both meso-2,3-dimercaptosuccinic acid (DMSA) coated Fe₃O₄ NPs (DMSA-Fe₃O₄ NPs) and DMSA-Fe₂O₃ NPs induced cell growth inhibition, while polyglucose sorbitol carboxymethyether coated Fe₂O₃ NPs(PSC-Fe₂O₃ NPs) did not. The PSC coating inhibited the cellular uptake of the IONPs. Both DMSA-Fe₃O₄ and DMSA-Fe₂O₃ NPs induced ferroptosis of HUVEC through upregulating phospholipid peroxides, which could be inhibited by typical ferroptosis inhibitors ferrostatin-1, Trolox and deferoxamine. Moreover, transforming growth factor beta 1 (TGFβ1) was upregulated by DMSA-Fe₃O₄ NPs at protein and gene level. The inhibitor of TGFβ1 receptor LY210 could reduce the effect. When being intravenously injected in mice, DMSA-Fe₃O₄ NPs were observed locating in the liver, increased the levels of lipid peroxidation (4-hydroxynonenal), acyl-CoA synthetase long-chain family member 4(ACSL4) and TGFβ1, indicating ferroptosis occurrence in vivo. The ferroptosis of vascular endothelial cells in exposure with IONPs depended on the surface coating and core chemistry of the NPs. Both DMSA-Fe₃O₄ NPs and DMSA-Fe₂O₃ NPs could induce the ferroptosis of endothelial cells, while PSC-Fe₂O₃ NPs did not induce ferroptosis and apoptosis possibly due to the very low cellular uptake. DMSA-Fe₃O₄ NPs and TGFβ1 formed feedforward loop to induce ferroptosis.

Keywords:

• Iron oxide nanoparticles
• endothelial cells
• ferroptosis
• TGFβ1
• lipid peroxidation

Ethics approval and consent to participate

Animal experiments were carried out in accordance with a protocol that was approved by the Institutional Animal Care and Use committee (Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and Peking Union Medical College, China). Female Balb/c mice were maintained at the institutional experimental animal center under specific pathogen-free conditions. The mice were fed with sterilized food and autoclaved tap water.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data Availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

The work was supported by the National Key R&D Program of China [2017YFA0205504] and CAMS Innovation Fund for Medical Science [CIFMS2016-I2M-3-004].