Interfering histone deacetylase 4 inhibits the proliferation of vascular smooth muscle cells via regulating MEG3/miR-125a-5p/IRF1

In this study, we investigated the role ofhistone deacetylase 4 (HDAC4) and MEG3/miR-125a-5p/interferonregulatoryfactor 1 (IRF1) on vascular smooth muscle cell (VSMCs)proliferation. Platelet derived growth factor (PDGF)-BB was used toinduce the proliferation and migration of VSMCs. The expressionsof MEG3, miR-125a-5p, HDAC4 and IRF1in VSMCs were detectedby qRT-PCR and western blot, respectively. ChIP assay was usedto determine the relationship between MEG3 and HDAC4. Doubleluciferase reporter assay was used to test the regulation betweenmiR-125-5p and IRF1. Results showed that PDGF-BB decreasedthe expression of MEG3 and IRF1, while increased the expressionof miR-125a-5p and HDAC4. In addition, HDAC4 knockdowninhibited the proliferation and migration of VSMCs via upregulatingMEG3 and downregulating miR-125a-5p. MiR-125a-5p inhibitorcould repress the proliferation and migration of VSMCs andalleviate intimal hyperplasia (IH) by directly upregulating IRF1expression. These results suggested that HDAC4 interferenceinhibited PDGF-BB-induced VSMCs proliferation via regulatingMEG3/miR-125a-5p/IRF1 axis, and then alleviated IH.

本研究探讨了组蛋白去乙酰化酶4（histone deacetylase 4, HDAC4）以及母系表达基因3（MEG3）/miR-125a-5p/干扰素调节因子1（interferon regulatory factor 1, IRF1）对血管平滑肌细胞（vascular smooth muscle cell, VSMCs）增殖的调控作用。采用血小板衍生生长因子-BB（platelet derived growth factor-BB, PDGF-BB）诱导VSMCs增殖与迁移。分别通过qRT-PCR与蛋白质印迹（western blot）实验检测VSMCs中MEG3、miR-125a-5p、HDAC4及IRF1的表达水平。采用染色质免疫沉淀（ChIP）实验验证MEG3与HDAC4的相互作用关系。采用双荧光素酶报告基因实验检测miR-125a-5p与IRF1的调控靶向关系。研究结果显示，PDGF-BB可下调MEG3与IRF1的表达，同时上调miR-125a-5p与HDAC4的表达。此外，敲低HDAC4可通过上调MEG3表达、下调miR-125a-5p表达的方式，抑制VSMCs的增殖与迁移。miR-125a-5p抑制剂可通过直接上调IRF1的表达，抑制VSMCs增殖迁移并减轻内膜增生（intimal hyperplasia, IH）。上述结果表明，干扰HDAC4可通过调控MEG3/miR-125a-5p/IRF1信号轴，抑制PDGF-BB诱导的VSMCs增殖，进而减轻内膜增生。