IRF4在血管损伤引起的内膜新生中的功能和机制研究

Neointima formation is a common pathogenesis of various vascular diseases, which is regulated by complex molecular network. Vascular smooth muscle cells (VSMCs) are critical for the neointima formation, modulation of the phenotypic switching, proliferation and migration of the VSMCs can effectively prevent the neointima formation. Interferon regulator factor-4 is a key transcriptional factor of innate immune network, which plays important roles in immune cell differentiation and maturation as well as innate immune response. Our previous studies showed that IRF4 regulated the pathogenesis of ischemic stroke and cardiac remodeling. However, the function of IRF4 in the neointima formation after vascular injury is still unknown. Our preliminary results indicate that IRF4 is expressed in the VSMCs, and is involved in the neointima formation after vascular injury. Using VSMC-specific IRF4 gene knockout mice and primary rat VSMCs, this proposal is aimed to elucidate the effect of IRF4 on the regulation of VSMCs functions, and the underlying mechanism by which IRF4 modulates the neointima formation. This work will provide theory evidence for searching for the novel therapeutic targets of vascular diseases relatesd to neointima formation

内膜新生是众多血管疾病发生的共同病理过程，其受到复杂的分子网络调控。血管平滑肌细胞在内膜新生中起着至关重要的重用，通过调节血管平滑肌细胞的表型转换、增殖和迁移能够有效防止内膜新生。干扰素调节因子-4（IRF4）是天然免疫网络中的核心转录因子，它在免疫细胞成熟分化以及调节天然免疫反应上有着重要的功能。我们以往的研究显示IRF4能够调控缺血性脑卒中和心脏重构的发生过程。然而，目前国内外对于IRF4在血管内膜新生的作用和机制尚无报道。我们前期的初步研究证实，IRF4在血管平滑肌细胞中表达，并且对血管损伤引起的内膜新生有重要影响。本项目拟通过平滑肌细胞特异性IRF4基因敲除小鼠和体外原代血管平滑肌细胞来系统地阐明IRF4在血管平滑肌细胞中的功能，以及其调节血管内膜新生的分子机制。为寻找与内膜新生相关血管疾病的新治疗靶点提供新的理论依据。

本项目通过利用平滑肌细胞特异性IRF4基因敲除及转基因小鼠构建血管损伤模型，证明了IRF4缺失促进内膜新生的形成，而IRF4过表达抑制内膜新生，即IRF4具有抑制血管损伤后新生内膜形成的功能。进一步的，通过生物信息学分析联合分子生物学实验手段证明了IRF4调控新生内膜形成与KLF4的表达相关，IRF4直接结合与KLF4的启动子区域以促进KLF4的表达。通过过表达KLF4可抑制由IRF4缺失导致的内膜增厚，即IRF4对血管损伤后新生内膜的形成的调控作用依赖于KLF4。这一研究明确了IRF4对血管损伤后内膜新生及内膜新生的具体调控作用，阐明了IRF4调控内膜新生的分子机制。