title: Cytotoxicity of CdTe quantum dots in human umbilical vein endothelial cells: the involvement of cellular uptake and induction of pro-apoptotic endoplasmic reticulum stress.
abstract: Cadmium telluride quantum dots (CdTe QDs) have been proposed to induce oxidative stress, which plays a crucial role in CdTe QDs-mediated mitochondrial-dependent apoptosis in human umbilical vein endothelial cells (HUVECs). However, the direct interactions of CdTe QDs with HUVECs and their potential impairment of other organelles like endoplasmic reticulum (ER) in HUVECs are poorly understood. In this study, we reported that the negatively charged CdTe QDs (-21.63±0.91 mV), with good dispersity and fluorescence stability, were rapidly internalized via endocytosis by HUVECs, as the notable internalization could be inhibited up to 95.52% by energy depletion (NaN3/deoxyglucose or low temperature). The endocytosis inhibitors (methyl-β-cyclodextrin, genistein, sucrose, chlorpromazine, and colchicine) dramatically decreased the uptake of CdTe QDs by HUVECs, suggesting that both caveolae/raft- and clathrin-mediated endocytosis were involved in the endothelial uptake of CdTe QDs. Using immunocytochemistry, a striking overlap of the internalized CdTe QDs and ER marker was observed, which indicates that QDs may be transported to ER. The CdTe QDs also caused remarkable ER stress responses in HUVECs, confirmed by significant dilatation of ER cisternae, upregulation of ER stress markers GRP78/GRP94, and activation of protein kinase RNA-like ER kinase-eIF2α-activating transcription factor 4 pathway (including phosphorylation of both protein kinase RNA-like ER kinase and eIF2α and elevated level of activating transcription factor 4). CdTe QDs further promoted an increased C/EBP homologous protein expression, phosphorylation of c-JUN NH2-terminal kinase, and cleavage of ER-resident caspase-4, while the specific inhibitor (SP600125, Z-LEVD-fmk, or salubrinal) significantly attenuated QDs-triggered apoptosis, indicating that all three ER stress-mediated apoptosis pathways were activated and the direct participation of ER in the CdTe QDs-caused apoptotic cell death in HUVECs. Our findings provide important new insights into QDs toxicity and reveal potential cardiovascular risks for the future applications of QDs.
authors.affiliation: Department of Biomedical Engineering, College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Basic Medical Sciences, College of Medicine, Shaoxing University, Shaoxing, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.affiliation: Department of Biomedical Engineering, College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, People's Republic of China.
authors.forename: Kezhou
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Biomedical Engineering, College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, People's Republic of China.
authors.forename: Yakun
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Biomedical Engineering, College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, People's Republic of China.
authors.forename: Mingen
authors.initials: M
authors.lastname: Xu
authors.affiliation: Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Department of Biomedical Engineering, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Department of Biomedical Engineering, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Zheng
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019187:Cadmium Compounds / Q000737:chemistry / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005453:Fluorescence; D019833:Genistein / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D045663:Quantum Dots / Q000737:chemistry; D013691:Tellurium / Q000737:chemistry / Q000494:pharmacology*; D013870:Thiomalates / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D019187:Cadmium Compounds; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D013870:Thiomalates; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C046062:2-thiomalic acid; D019833:Genistein; D019892:eIF-2 Kinase; D013691:Tellurium; D003078:Colchicine; C028337:cadmium telluride
keywords: ER stress; apoptosis; endocytosis; human umbilical vein endothelial cells; quantum dots