National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
National Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
J Mol Cell Cardiol. 2024 May;190:62-75. doi: 10.1016/j.yjmcc.2024.04.004. Epub 2024 Apr 6.
Intimal hyperplasia is a complicated pathophysiological phenomenon attributable to in-stent restenosis, and the underlying mechanism remains unclear. Interleukin enhancer-binding factor 3 (ILF3), a double-stranded RNA-binding protein involved in regulating mRNA stability, has been recently demonstrated to assume a crucial role in cardiovascular disease; nevertheless, its impact on intimal hyperplasia remains unknown. In current study, we used samples of human restenotic arteries and rodent models of intimal hyperplasia, we found that vascular smooth muscle cell (VSMC) ILF3 expression was markedly elevated in human restenotic arteries and murine ligated carotid arteries. SMC-specific ILF3 knockout mice significantly suppressed injury induced neointimal formation. In vitro, platelet-derived growth factor type BB (PDGF-BB) treatment elevated the level of VSMC ILF3 in a dose- and time-dependent manner. ILF3 silencing markedly inhibited PDGF-BB-induced phenotype switching, proliferation, and migration in VSMCs. Transcriptome sequencing and RNA immunoprecipitation sequencing depicted that ILF3 maintained its stability upon binding to the mRNA of the high-mobility group box 1 protein (HMGB1), thereby exerting an inhibitory effect on the transcription of dual specificity phosphatase 16 (DUSP16) through enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Therefore, the results both in vitro and in vivo indicated that the loss of ILF3 in VSMC ameliorated neointimal hyperplasia by regulating the STAT3/DUSP16 axis through the degradation of HMGB1 mRNA. Our findings revealed that vascular injury activates VSMC ILF3, which in turn promotes intima formation. Consequently, targeting specific VSMC ILF3 may present a potential therapeutic strategy for ameliorating cardiovascular restenosis.
内膜增生是导致支架内再狭窄的一种复杂的病理生理现象，其潜在机制尚不清楚。白细胞介素增强因子 3（ILF3）是一种双链 RNA 结合蛋白，参与调节 mRNA 稳定性，最近被证明在心血管疾病中发挥重要作用；然而，其对内膜增生的影响尚不清楚。在本研究中，我们使用了人再狭窄动脉和内膜增生的啮齿动物模型的样本，发现人再狭窄动脉和小鼠结扎颈动脉中的血管平滑肌细胞（VSMC）ILF3 表达明显升高。平滑肌细胞特异性 ILF3 敲除小鼠显著抑制了损伤诱导的新生内膜形成。在体外，血小板衍生生长因子 BB（PDGF-BB）处理以剂量和时间依赖的方式升高 VSMC ILF3 水平。ILF3 沉默显著抑制了 PDGF-BB 诱导的 VSMCs 表型转换、增殖和迁移。转录组测序和 RNA 免疫沉淀测序表明，ILF3 与高迁移率族盒 1 蛋白（HMGB1）的 mRNA 结合后保持其稳定性，从而通过增强信号转导和转录激活因子 3（STAT3）的磷酸化对双特异性磷酸酶 16（DUSP16）的转录产生抑制作用。因此，体内外的结果均表明，VSMC 中 ILF3 的缺失通过降解 HMGB1 mRNA 调节 STAT3/DUSP16 轴来改善新生内膜增生。我们的研究结果表明，血管损伤激活了 VSMC 的 ILF3，进而促进了内膜形成。因此，靶向特定的 VSMC ILF3 可能为改善心血管再狭窄提供一种潜在的治疗策略。
