Ye Bozhi, Wu Zi-Heng, Tsui Tung Yu, Zhang Bao-Fu, Su Xiang, Qiu Yi-Hui, Zheng Xiang-Tao
Department of Cardiology, the Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China.
Department of Vascular Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Mol Ther Nucleic Acids. 2020 Jun 5;20:62-72. doi: 10.1016/j.omtn.2020.01.032. Epub 2020 Feb 4.
Inflammation and proliferation of vascular smooth muscle cells (VSMCs) are the key events in intimal hyperplasia. This study aimed to explore the mechanism by which long non-coding RNA (lncRNA) KCNQ1OT1 affects VSMC inflammation and proliferation in this context. A vein graft (VG) model was established in mice to introduce intimal hyperplasia. Isolated normal VSMCs were induced with platelet-derived growth factor type BB (PDGF-BB), and the cell proliferation, migration, and secretion of inflammatory factors were determined. The results showed that KCNQ1OT1 was downregulated in the VSMCs from mice with intimal hyperplasia and in the PDGF-BB-treated VSMCs, and such downregulation of KCNQ1OT1 resulted from the increased methylation level in the KCNQ1OT1 promoter. Overexpressing KCNQ1OT1 suppressed PDFG-BB-induced VSMC proliferation, migration, and secretion of inflammatory factors. In VSMCs, KCNQ1OT1 bound to the nuclear transcription factor kappa Ba (IκBa) protein and increased the cellular IκBa level by reducing phosphorylation and promoting ubiquitination of the IκBa protein. Meanwhile, KCNQ1OT1 promoted the expression of IκBa by sponging miR-221. The effects of KCNQ1OT1 knockdown on promoting VSMC proliferation, migration, and secretion of inflammatory factors were abolished by IκBa overexpression. The roles of KCNQ1OT1 in reducing the intimal area and inhibiting IκBa expression were proved in the VG mouse model after KCNQ1OT1 overexpression. In conclusion, KCNQ1OT1 attenuated intimal hyperplasia by suppressing the inflammation and proliferation of VSMCs, in which the mechanism upregulated IκBa expression by binding to the IκBa protein and sponging miR-221.
血管平滑肌细胞（VSMC）的炎症和增殖是内膜增生的关键事件。本研究旨在探讨长链非编码RNA（lncRNA）KCNQ1OT1在此背景下影响VSMC炎症和增殖的机制。在小鼠中建立静脉移植物（VG）模型以引发内膜增生。用血小板衍生生长因子BB型（PDGF-BB）诱导分离的正常VSMC，并测定细胞增殖、迁移和炎性因子分泌。结果显示，在内膜增生小鼠的VSMC以及PDGF-BB处理的VSMC中，KCNQ1OT1表达下调，且KCNQ1OT1的这种下调是由KCNQ1OT1启动子甲基化水平升高所致。过表达KCNQ1OT1可抑制PDGF-BB诱导的VSMC增殖、迁移和炎性因子分泌。在VSMC中，KCNQ1OT1与核转录因子κBα（IκBα）蛋白结合，并通过减少IκBα蛋白的磷酸化和促进其泛素化来提高细胞内IκBα水平。同时，KCNQ1OT1通过吸附miR-221促进IκBα的表达。IκBα过表达消除了KCNQ1OT1敲低对促进VSMC增殖、迁移和炎性因子分泌的作用。在KCNQ1OT1过表达后的VG小鼠模型中，证实了KCNQ1OT1在减少内膜面积和抑制IκBα表达方面的作用。总之，KCNQ1OT1通过抑制VSMC的炎症和增殖来减轻内膜增生，其机制是通过与IκBα蛋白结合并吸附miR-221上调IκBα表达。
