Department of Biotechnology, Jinan University, Guangzhou, Guangdong Province, China.
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA.
Environ Health Perspect. 2019 Jul;127(7):77003. doi: 10.1289/EHP4538. Epub 2019 Jul 5.
Arsenic (As) is a well-known environmental contaminant. Chronic exposure to As is known to increase the risk of cardiovascular diseases, including atherosclerosis, hypertension, diabetes, and stroke. However, the detailed mechanisms by which As causes vascular dysfunction involving endothelial integrity and permeability is unclear.
Our goal was to investigate how exposure to As leads to endothelial dysfunction.
Arsenic trioxide (ATO) was used to investigate the effects and mechanisms by which exposure to As leads to endothelial dysfunction using a mouse model and cultured endothelial cell monolayers.
Compared with the controls, mice exposed chronically to As (10 ppb in drinking water supplied by ATO) exhibited greater vascular permeability to Evans blue dye and fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA). In addition, endothelial monolayers treated with ATO ([Formula: see text] As) exhibited greater intracellular gaps and permeability to low-density lipoprotein or transmigrating THP-1 cells. Furthermore, activity and protein levels of calpain-1 (CAPN-1) were significantly higher in aortas and human umbilical vein endothelial cells (HUVECs) treated with ATO. These results were consistent with effects of ATO treatment and included a rapid increase of intracellular calcium ([Formula: see text]) and higher levels of CAPN-1 in the plasma membrane. Endothelial cell dysfunction and the proteolytic disorganization of vascular endothelial cadherin (VE-cadherin) in HUVECs in response to ATO were partially mitigated by treatment with a CAPN-1 inhibitor (ALLM) but not a CAPN-2 inhibitor (Z-LLY-FMK).
This study found that in mice and HUVEC models, exposure to ATO led to CAPN-1 activation by increasing [Formula: see text] and CAPN-1 translocation to the plasma membrane. The study also suggested that inhibitor treatment may have a role in preventing the vascular endothelial dysfunction associated with As exposure. The findings presented herein suggest that As-induced endothelial dysfunction involves the hyperactivation of the CAPN proteolytic system. https://doi.org/10.1289/EHP4538.
砷（As）是一种众所周知的环境污染物。已知慢性暴露于砷会增加心血管疾病的风险，包括动脉粥样硬化、高血压、糖尿病和中风。然而，砷导致血管功能障碍涉及内皮完整性和通透性的详细机制尚不清楚。
我们的目标是研究砷暴露如何导致内皮功能障碍。
使用三氧化二砷（ATO）在小鼠模型和培养的内皮细胞单层中研究砷暴露导致内皮功能障碍的影响和机制。
与对照组相比，慢性暴露于砷（饮用水中提供的 10 ppb 的 ATO）的小鼠对 Evans 蓝染料和异硫氰酸荧光素标记的牛血清白蛋白（FITC-BSA）的血管通透性更大。此外，用 ATO 处理的内皮单层（[公式：见文本]As）显示出更大的细胞内间隙和对低密度脂蛋白或穿透性 THP-1 细胞的通透性。此外，ATO 处理的主动脉和人脐静脉内皮细胞（HUVEC）中的钙蛋白酶-1（CAPN-1）活性和蛋白水平显着升高。这些结果与 ATO 处理的效果一致，包括细胞内钙 ([Formula: see text]) 的快速增加和质膜中 CAPN-1 的更高水平。ATO 处理后，HUVEC 中的内皮细胞功能障碍和血管内皮钙粘蛋白（VE-cadherin）的蛋白水解解聚部分减轻了 CAPN-1 抑制剂（ALLM）的治疗，但 CAPN-2 抑制剂（Z-LLY-FMK）的治疗没有减轻。
本研究发现，在小鼠和 HUVEC 模型中，ATO 暴露通过增加 [Formula: see text] 和 CAPN-1 向质膜的易位导致 CAPN-1 激活。该研究还表明，抑制剂治疗可能在预防与砷暴露相关的血管内皮功能障碍方面发挥作用。本研究结果表明，砷诱导的内皮功能障碍涉及 CAPN 蛋白水解系统的过度激活。https://doi.org/10.1289/EHP4538.
