慢性低水平镉暴露经由ICAM-1和VCAM-1糖基化修饰促进血管内皮炎症的研究

Chronic exposure to low-level cadmium (Cd) (well below toxic concentrations) was shown to increase the expression of intercellular cell adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), contributing to proinflammatory response in vascular endothelium. However, it is unknown whether this Cd-induced effect on inflammation is depended on activating the glycosylation of cell adhesion molecules, which is still an ongoing issue in the mechanism of atherosclerotic pathogenesis promoted by low-level Cd-related vascular endothelial dysfunction. Our findings strongly suggest that low-dose Cd may exert an effect, through the hexosamine biosynthesis pathway (HBP), on the glycosylation of ICAM-1 and VCAM-1 to elevate the expression of cell adhesion molecules. Therefore, we take the following measures to aim to: ① confirm whether the proinflammatory response is induced by the stimulus effect of low-dose Cd on the ICAM-1 and VCAM-1 glycosylation, through the HBP, in vascular endothelial cells. ② examine whether low doses of Cd promote the development of chronic inflammation of vascular endothelium via the glycosylation of ICAM-1 and VCAM-1 in ApoE-/- mice. ③ evaluate the dose-response relationship between low-level Cd exposure and the levels of cell adhesion molecules in general population. We finally generalize the above results to systematically conclude whether chronic exposure to low-level Cd could promote vascular chronic inflammation via the glycosylation of ICAM-1 and VCAM-1. The conclusions would provide a new insight into the mechanisms underlying the risk effect of chronic low-level exposure to Cd on early cardiovascular lesions.

慢性低水平镉（Cd）暴露可提高血管内皮细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）的表达，促进炎症反应。但目前不清楚Cd的这种促炎效应，是否为经由影响黏附分子的糖基化修饰而达到。这是低水平Cd损害血管内皮促进动脉粥样硬化发展的机制研究中亟待明确的问题。我们前期研究提示低剂量Cd可能通过己糖胺通路影响ICAM-1、VCAM-1糖基化修饰，促进这些黏附分子表达。本研究在此基础上拟通过：①内皮细胞实验明确低剂量Cd是否通过己糖胺通路介入ICAM-1、VCAM-1糖基化修饰，促进炎症反应；②ApoE-/-小鼠实验评价低剂量Cd经由ICAM-1、VCAM-1糖基化修饰，促进血管内皮慢性炎症发展；③人群研究评价低水平Cd与黏附分子的剂量反应关系。验证Cd经由ICAM-1、VCAM-1糖基化修饰产生致炎效应的可能性。本研究可对低水平Cd增加心血管早期病理风险的机制有新的认识。

慢性镉（Cd）暴露即使是低水平（尿Cd浓度< 5 μg/g肌酐）范围，也能增加不同病理阶段的动脉粥样硬化性心血管事件风险。动脉粥样硬化发展主要病理性驱动因素之一来自血管内皮慢性炎症，我们前期工作提示暴露于低剂量Cd产生促炎反应的血管内皮细胞表型可能与蛋白糖基化有关。在此基础上，本研究从三个方面检验了Cd经由血管内皮炎症黏附分子ICAM-1、VCAM-1糖基化修饰产生致炎效应的可能性：（1）人群研究评价低水平Cd暴露与黏附分子的剂量反应关系；（2）细胞实验明确低剂量Cd是否可通过己糖胺合成通路（HBP）影响黏附分子表达；（3）动物实验证明低剂量Cd经由黏附分子糖基化修饰促进血管内皮炎症。本研究发现，慢性低水平Cd暴露，不仅与循环ICAM-1、VCAM-1升高存在剂量反应关系，也普遍与心血管亚临床期病理及综合风险上升有关，此外，VCAM-1尚具有低水平Cd促心血管风险上升的中介作用。在机制方面，低水平Cd提高血管内皮ICAM-1、VCAM-1的表达，这种促炎作用与HBP的激活有关，通过抑制HBP，限制后继的糖基化修饰可减弱黏附分子的表达。本研究通过揭示低水平Cd、糖基化修饰与促炎效应之间的关系，对低水平Cd影响心血管系统早期病理有新的认识，有助于为环境低水平Cd暴露有关的动脉粥样硬化性心血管病防治提供新的思路。