Laboratory of Microvascular Medicine, Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan, Shandong 250014, China.
Department of Cardiology, Provincial Hospital Affiliated to Shandong University, 324 Jingwu Road, Jinan, Shandong 250021, China.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):447-52. doi: 10.1016/j.bbrc.2014.05.140. Epub 2014 Jun 6.
The vasculature of various organs is a targeted by the environmental toxin, cadmium (Cd). However, mechanisms leading to pathological conditions are poorly understood. In the present study, we examined the effect of cadmium chloride (CdCl2) on human umbilical vein endothelial cells (HUVECs). At 4 μM, CdCl2 induced a hyper-permeability defect in HUVECs, but not the inhibition of cell growth up to 24h. This effect of CdCl2 was dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. The p38 MAPK inhibitor SB203850 suppressed the CdCl2-induced alteration in trans-endothelial electrical resistance in HUVEC monolayers, a model measurement of vascular endothelial barrier integrity. SB203850 also inhibited the Cd-induced membrane dissociation of vascular endothelial (VE) cadherin and β-catenin, the important components of the adherens junctional complex. In addition, SB203850 reduces the Cd-induced expression and secretion of tumor necrosis factor α (TNF-α). Taken together, our findings suggest that Cd induces vascular hyper-permeability and disruption of endothelial barrier integrity through stimulation of p38 MAPK signaling.
各种器官的脉管系统是环境毒素镉 (Cd) 的靶标。然而，导致病理状况的机制尚不清楚。在本研究中，我们检查了氯化镉 (CdCl2) 对人脐静脉内皮细胞 (HUVEC) 的影响。在 4 μM 时，CdCl2 诱导 HUVEC 出现高通透性缺陷，但在 24 小时内不会抑制细胞生长。这种 CdCl2 的作用依赖于 p38 丝裂原活化蛋白激酶 (MAPK) 途径的激活。p38 MAPK 抑制剂 SB203850 抑制了 CdCl2 诱导的 HUVEC 单层跨内皮电阻的改变，这是血管内皮屏障完整性的模型测量。SB203850 还抑制了 Cd 诱导的血管内皮 (VE) 钙粘蛋白和 β-连环蛋白的膜解离，VE 钙粘蛋白和 β-连环蛋白是黏着连接复合体的重要组成部分。此外，SB203850 降低了 Cd 诱导的肿瘤坏死因子 α (TNF-α) 的表达和分泌。总之，我们的研究结果表明，Cd 通过刺激 p38 MAPK 信号通路诱导血管通透性增加和内皮屏障完整性破坏。
