Department of Environmental Health, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan.
Department of Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
Toxicol Appl Pharmacol. 2022 Jan 1;434:115802. doi: 10.1016/j.taap.2021.115802. Epub 2021 Nov 22.
Cadmium is an environmental pollutant that adversely affects various organs in the human body and is a well-known risk factor for cardiovascular diseases. These disorders are caused by the dysfunction of the vascular endothelial cells that cover the luminal surface of blood vessels. The ZIP transporter ZIP8 is one of the primary importers of cadmium, and its expression appears to be important for the sensitivity of vascular endothelial cells to cadmium. In the present study, we investigated the influence of ZIP8 on cadmium-induced cytotoxicity in vascular endothelial cells, the induction of ZIP8 expression by cadmium, and its action mechanism in vascular endothelial cells. The study revealed that: (1) cadmium cytotoxicity in vascular endothelial cells was potentiated by the overexpression of ZIP8, and the intracellular accumulation of cadmium in the cells was increased; (2) cadmium highly induced the expression of ZIP8, but not other ZIPs; (3) lead and methylmercury moderately induced ZIP8 expression, but the other tested metals did not; (4) the induction of ZIP8 expression by cadmium was mediated by both NF-κB and JNK signaling, and the accumulation of NF-κB in the nucleus was regulated by JNK signaling. Particularly, it was found that cadmium activated NF-κB to transfer it into nuclei and activated JNK to stabilize NF-κB in nuclei, resulting in the induction of ZIP8 expression. This induction appears to be crucial for cadmium cytotoxicity in vascular endothelial cells.
镉是一种环境污染物，会对人体的各种器官产生不良影响，是心血管疾病的一个已知危险因素。这些疾病是由覆盖在血管腔表面的血管内皮细胞功能障碍引起的。ZIP 转运蛋白 ZIP8 是镉的主要摄取体之一，其表达似乎对血管内皮细胞对镉的敏感性很重要。在本研究中，我们研究了 ZIP8 对血管内皮细胞中镉诱导的细胞毒性、镉诱导 ZIP8 表达及其在血管内皮细胞中的作用机制的影响。研究表明：(1) 过表达 ZIP8 增强了镉对血管内皮细胞的细胞毒性，细胞内镉的积累增加；(2) 镉高度诱导 ZIP8 的表达，但不诱导其他 ZIPs；(3) 铅和甲基汞适度诱导 ZIP8 的表达，但其他测试的金属没有；(4) 镉诱导 ZIP8 表达是通过 NF-κB 和 JNK 信号通路介导的，JNK 信号通路调节 NF-κB 进入细胞核。特别是，研究发现镉激活 NF-κB 并将其转移到细胞核中，激活 JNK 稳定 NF-κB 在细胞核中的位置，从而诱导 ZIP8 的表达。这种诱导对于镉诱导的血管内皮细胞毒性似乎是至关重要的。
