Xu Dan, Guo Yubing, Liu Tong, Li Shuai, Sun Yeqing
Institute of Environmental Systems Biology, Environment Science and Engineering College, Dalian Maritime University, Linghai Road 1, Dalian, 116026, PR China.
Toxicol Lett. 2017 Mar 5;269:33-40. doi: 10.1016/j.toxlet.2017.01.014. Epub 2017 Feb 2.
microRNAs (miRNAs) function in the posttranscriptional gene regulation, providing new insights into the epigenetic mechanism of toxicity induced by environmental pollutants. miR-22 was discovered to regulate cell proliferation and apoptosis in response to environmental toxicants. We have reported that endosulfan can cause endothelial toxicity in human umbilical vein endothelial cells (HUVECs). In the present study, we investigated the involvement of miR-22 in endosulfan-induced endothelial dysfunction. The expression level of miR-22 was increased in a dose-dependent manner by endosulfan exposure. Overexpression of miR-22 induced apoptosis and inflammation in HUVECs. Anti-miR-22 transfection significantly attenuated the increase in the percentage of apoptotic cells, caspase-3 activity and Interleukin (IL)-6, 8 mRNA levels in endosulfan-exposed HUVECs. Luciferase reporter assay confirmed that SRF and STAG2 were novel direct targets of miR-22. Endosulfan decreased mRNA expression of both SRF and STAG2, but only suppressed protein expression of SRF. Knockdown of SRF via siRNAs resulted in apoptosis and inflammation whereas STAG2 siRNAs only caused abnormal mitosis in HUVECs. Taken together, these findings will shed light on the role and mechanism of miR-22 in endosulfan-induced endothelial dysfunction via SRF in HUVECs.
微小RNA（miRNA）在转录后基因调控中发挥作用，为环境污染物诱导毒性的表观遗传机制提供了新的见解。已发现miR-22可响应环境毒物调节细胞增殖和凋亡。我们曾报道，硫丹可导致人脐静脉内皮细胞（HUVECs）出现内皮毒性。在本研究中，我们调查了miR-22在硫丹诱导的内皮功能障碍中的作用。硫丹暴露以剂量依赖的方式增加了miR-22的表达水平。miR-22的过表达诱导了HUVECs的凋亡和炎症。抗miR-22转染显著减弱了硫丹暴露的HUVECs中凋亡细胞百分比、半胱天冬酶-3活性以及白细胞介素（IL）-6、8 mRNA水平的升高。荧光素酶报告基因检测证实，血清反应因子（SRF）和粘连蛋白2（STAG2）是miR-22新的直接靶点。硫丹降低了SRF和STAG2的mRNA表达，但仅抑制了SRF的蛋白表达。通过小干扰RNA（siRNA）敲低SRF会导致凋亡和炎症，而STAG2的siRNA仅在HUVECs中引起异常有丝分裂。综上所述，这些发现将阐明miR-22在硫丹通过SRF诱导HUVECs内皮功能障碍中的作用和机制。
