Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells

Hui He,1,* Zhen Zou,2,* Bin Wang,2 Ge Xu,2 Chengzhi Chen,3 Xia Qin,1 Chao Yu,1 Jun Zhang2 1College of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China; 2Institute of Life Sciences, Chongqing Medical University, Chongqing, People’s Republic of China; 3...

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Autores principales:	He H, Zou Z, Wang B, Xu G, Chen C, Qin X, Yu C, Zhang J
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	cuonps vascular endothelial cell death oxidative stress dna damage p38 mapk activation copper ions release. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/a6f5234edde24fdf8ee5b10635d50dce
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spelling	oai:doaj.org-article:a6f5234edde24fdf8ee5b10635d50dce2021-12-02T13:12:07ZCopper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells1178-2013https://doaj.org/article/a6f5234edde24fdf8ee5b10635d50dce2020-05-01T00:00:00Zhttps://www.dovepress.com/copper-oxide-nanoparticles-induce-oxidative-dna-damage-and-cell-death--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Hui He,1,* Zhen Zou,2,* Bin Wang,2 Ge Xu,2 Chengzhi Chen,3 Xia Qin,1 Chao Yu,1 Jun Zhang2 1College of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China; 2Institute of Life Sciences, Chongqing Medical University, Chongqing, People’s Republic of China; 3School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao Yu; Jun Zhang Email yuchaom@163.com; zhangjun@cqmu.edu.cnBackground: Inhaled nanoparticles can cross pulmonary air–blood barrier into circulation and cause vascular endothelial injury and progression of cardiovascular disease. However, the molecular mechanism underlying the vascular toxicity of copper oxide nanoparticles (CuONPs) remains unclear. We have recently demonstrated that the release of copper ions and the accumulation of superoxide anions contributed to CuONPs-induced cell death in human umbilical vein endothelial cells (HUVECs). Herein, we further demonstrate the mechanism underlying copper ions-induced cell death in HUVECs.Methods and Results: CuONPs were suspended in culture medium and vigorously vortexed for several seconds before exposure. After treatment with CuONPs, HUVECs were collected, and cell function assays were conducted to elucidate cellular processes including cell viability, oxidative stress, DNA damage and cell signaling pathways. We demonstrated that CuONPs uptake induced DNA damage in HUVECs as evidenced by γH2AX foci formation and increased phosphorylation levels of ATR, ATM, p53 and H2AX. Meanwhile, we showed that CuONPs exposure induced oxidative stress, indicated by the increase of cellular levels of superoxide anions, the upregulation of protein levels of heme oxygenase-1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), the elevation of the levels of malondialdehyde (MDA), but the reduction of glutathione to glutathione disulfide ratio. We also found that antioxidant N-acetyl-L-cysteine (NAC) could ameliorate CuONPs-induced oxidative stress and cell death. Interestingly, we demonstrated that p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated in CuONPs-treated HUVECs, while p38α MAPK knockdown by siRNA significantly rescued HUVECs from CuONPs-induced DNA damage and cell death. Importantly, we showed that copper ions chelator tetrathiomolybdate (TTM) could alleviate CuONPs-induced oxidative stress, DNA damage, p38 MAPK pathway activation and cell death in HUVECs.Conclusion: We demonstrated that CuONPs induced oxidative DNA damage and cell death via copper ions-mediated p38 MAPK activation in HUVECs, suggesting that the release of copper ions was the upstream activator for CuONPs-induced vascular endothelial toxicity, and the copper ions chelator TTM can alleviate CuONPs-associated cardiovascular disease.Keywords: CuONPs, vascular endothelial cell death, oxidative stress, DNA damage, p38 MAPK activation, copper ions releaseHe HZou ZWang BXu GChen CQin XYu CZhang JDove Medical Pressarticlecuonpsvascular endothelial cell deathoxidative stressdna damagep38 mapk activationcopper ions release.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 15, Pp 3291-3302 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	cuonps vascular endothelial cell death oxidative stress dna damage p38 mapk activation copper ions release. Medicine (General) R5-920
spellingShingle	cuonps vascular endothelial cell death oxidative stress dna damage p38 mapk activation copper ions release. Medicine (General) R5-920 He H Zou Z Wang B Xu G Chen C Qin X Yu C Zhang J Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells
description	Hui He,1,* Zhen Zou,2,* Bin Wang,2 Ge Xu,2 Chengzhi Chen,3 Xia Qin,1 Chao Yu,1 Jun Zhang2 1College of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China; 2Institute of Life Sciences, Chongqing Medical University, Chongqing, People’s Republic of China; 3School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao Yu; Jun Zhang Email yuchaom@163.com; zhangjun@cqmu.edu.cnBackground: Inhaled nanoparticles can cross pulmonary air–blood barrier into circulation and cause vascular endothelial injury and progression of cardiovascular disease. However, the molecular mechanism underlying the vascular toxicity of copper oxide nanoparticles (CuONPs) remains unclear. We have recently demonstrated that the release of copper ions and the accumulation of superoxide anions contributed to CuONPs-induced cell death in human umbilical vein endothelial cells (HUVECs). Herein, we further demonstrate the mechanism underlying copper ions-induced cell death in HUVECs.Methods and Results: CuONPs were suspended in culture medium and vigorously vortexed for several seconds before exposure. After treatment with CuONPs, HUVECs were collected, and cell function assays were conducted to elucidate cellular processes including cell viability, oxidative stress, DNA damage and cell signaling pathways. We demonstrated that CuONPs uptake induced DNA damage in HUVECs as evidenced by γH2AX foci formation and increased phosphorylation levels of ATR, ATM, p53 and H2AX. Meanwhile, we showed that CuONPs exposure induced oxidative stress, indicated by the increase of cellular levels of superoxide anions, the upregulation of protein levels of heme oxygenase-1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), the elevation of the levels of malondialdehyde (MDA), but the reduction of glutathione to glutathione disulfide ratio. We also found that antioxidant N-acetyl-L-cysteine (NAC) could ameliorate CuONPs-induced oxidative stress and cell death. Interestingly, we demonstrated that p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated in CuONPs-treated HUVECs, while p38α MAPK knockdown by siRNA significantly rescued HUVECs from CuONPs-induced DNA damage and cell death. Importantly, we showed that copper ions chelator tetrathiomolybdate (TTM) could alleviate CuONPs-induced oxidative stress, DNA damage, p38 MAPK pathway activation and cell death in HUVECs.Conclusion: We demonstrated that CuONPs induced oxidative DNA damage and cell death via copper ions-mediated p38 MAPK activation in HUVECs, suggesting that the release of copper ions was the upstream activator for CuONPs-induced vascular endothelial toxicity, and the copper ions chelator TTM can alleviate CuONPs-associated cardiovascular disease.Keywords: CuONPs, vascular endothelial cell death, oxidative stress, DNA damage, p38 MAPK activation, copper ions release
format	article
author	He H Zou Z Wang B Xu G Chen C Qin X Yu C Zhang J
author_facet	He H Zou Z Wang B Xu G Chen C Qin X Yu C Zhang J
author_sort	He H
title	Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells
title_short	Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells
title_full	Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells
title_fullStr	Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells
title_full_unstemmed	Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells
title_sort	copper oxide nanoparticles induce oxidative dna damage and cell death via copper ion-mediated p38 mapk activation in vascular endothelial cells
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/a6f5234edde24fdf8ee5b10635d50dce
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Copper Oxide Nanoparticles Induce Oxidative DNA Damage and Cell Death via Copper Ion-Mediated P38 MAPK Activation in Vascular Endothelial Cells

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