Faculty of Pharmaceutical Sciences, Toho University.
Faculty of Pharmaceutical Sciences, Tokyo University of Science.
J Toxicol Sci. 2021;46(5):249-253. doi: 10.2131/jts.46.249.
Modulation of the blood coagulation fibrinolytic system is an essential function of vascular endothelial cells. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) are major fibrinolytic regulatory proteins synthesized by vascular endothelial cells; fibrinolytic activity is dependent on the balance between these proteins. Previously, we have reported that cadmium, an initiator of ischemic heart disease, induces PAI-1 expression and suppresses fibrinolytic activity in cultured human vascular endothelial cells. However, the key molecules involved in cadmium-induced PAI-1 induction remain unclear. Herein, we investigated the contribution of Smad2 and Smad3, transcriptional factors involved in PAI-1 induction via transforming growth factor-β, using the human vascular endothelial cell line EA.hy926 cells in culture. Our findings indicated that cadmium induces PAI-1 expression without affecting t-PA expression up to 20 µM, a non-cytotoxic concentration, and PAI-1 induction by cadmium is partly mediated via Smad2 and Smad3. This study provides a possible mechanism underlying cadmium-induced vascular disorders.
血液凝固-纤维蛋白溶解系统的调节是血管内皮细胞的基本功能。组织型纤溶酶原激活物（t-PA）和纤溶酶原激活物抑制剂-1（PAI-1）是血管内皮细胞合成的主要纤维蛋白溶解调节蛋白；纤维蛋白溶解活性依赖于这些蛋白之间的平衡。此前，我们曾报道过，缺血性心脏病的启动子镉诱导培养的人血管内皮细胞中 PAI-1 的表达，并抑制纤维蛋白溶解活性。然而，镉诱导 PAI-1 诱导的关键分子尚不清楚。在此，我们使用人血管内皮细胞系 EA.hy926 细胞，研究了转化生长因子-β（TGF-β）诱导 PAI-1 表达的转录因子 Smad2 和 Smad3 在镉诱导 PAI-1 表达中的作用。我们的研究结果表明，镉在非细胞毒性浓度 20µM 以下诱导 PAI-1 表达而不影响 t-PA 表达，镉诱导的 PAI-1 表达部分通过 Smad2 和 Smad3 介导。本研究为镉诱导的血管紊乱提供了一种可能的机制。
