Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University, 310003, Hangzhou, China.
Institute of Translational Medicine, Zhejiang University, 310029, Hangzhou, China.
Sci Rep. 2017 Nov 1;7(1):14811. doi: 10.1038/s41598-017-13694-5.
Cadmium (Cd) is a harmful heavy metal that results in vascular diseases such as atherosclerosis. Prior evidence revealed that Cd induced endothelial cell (EC) death and dysfunction, supporting that ECs are a primary target of Cd-induced toxicity, and can cause severe pathologies of vascular diseases. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanisms of Cd-induced endothelial toxicity in a human model system of H9 human pluripotent stem cell-derived endothelial cells (H9-ECs). We showed that H9-ECs were susceptible to CdCl induction, leading to detrimental changes of cell structure and significantly elevated level of apoptosis. We demonstrated that CdCl-treated H9-ECs gave rise to a clear EC dysfunction phenotype and significantly differential transcriptomic profile. Signaling pathway analysis revealed that P38 or ERK signaling pathway is critical to cadmium-induced EC apoptosis and dysfunction, and inhibition of P38 or ERK effectively rescued CdCl-induced endothelial toxicity in H9-ECs. Conclusively, hPSC-ECs can be a reliable model to recapitulate the EC pathological features and transcriptomic profile, which may provide a unique platform for understanding the cellular and molecular mechanisms of Cd-induced endothelial toxicity and for identifying therapeutic drugs for Cd-induced vascular diseases.
镉（Cd）是一种有害的重金属，可导致血管疾病，如动脉粥样硬化。先前的证据表明，镉诱导内皮细胞（EC）死亡和功能障碍，支持 EC 是镉诱导毒性的主要靶标，并可导致血管疾病的严重病变。然而，其潜在机制尚不清楚。在这项研究中，我们在人多能干细胞衍生的内皮细胞（H9-ECs）的人类模型系统中研究了镉诱导的内皮毒性的机制。我们表明，H9-ECs 易受 CdCl 诱导，导致细胞结构的有害变化和凋亡水平的显著升高。我们证明，CdCl 处理的 H9-ECs 产生了明显的 EC 功能障碍表型和明显不同的转录组谱。信号通路分析表明，P38 或 ERK 信号通路对镉诱导的 EC 凋亡和功能障碍至关重要，抑制 P38 或 ERK 可有效挽救 H9-ECs 中的镉诱导的内皮毒性。总之，hPSC-ECs 可以作为一种可靠的模型来重现 EC 的病理特征和转录组谱，这可能为理解镉诱导的内皮毒性的细胞和分子机制以及鉴定治疗镉诱导的血管疾病的药物提供一个独特的平台。
