Huang Ling, Zhang Shu-Min, Zhang Peng, Zhang Xiao-Jing, Zhu Li-Hua, Chen Ke, Gao Lu, Zhang Yan, Kong Xiang-Jie, Tian Song, Zhang Xiao-Dong, Li Hongliang
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.).
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China (X.J.Z.).
J Am Heart Assoc. 2014 Oct 10;3(5):e001309. doi: 10.1161/JAHA.114.001309.
Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factor family, plays important roles in innate immunity and immune cell differentiation. However, the role of IRF7 in neointima formation is currently unknown.
Significant decreases in IRF7 expression were observed in vascular smooth muscle cells (VSMCs) following carotid artery injury in vivo and platelet-derived growth factor-BB (PDGF-BB) stimulation in vitro. Compared with non-transgenic (NTG) controls, SMC-specific IRF7 transgenic (IRF7-TG) mice displayed reduced neointima formation and VSMC proliferation in response to carotid injury, whereas a global knockout of IRF7 (IRF7-KO) resulted in the opposite effect. Notably, a novel IRF7-KO rat strain was successfully generated and used to further confirm the effects of IRF7 deletion on the acceleration of intimal hyperplasia based on a balloon injury-induced vascular lesion model. Mechanistically, IRF7's inhibition of carotid thickening and the expression of VSMC proliferation markers was dependent on the interaction of IRF7 with activating transcription factor 3 (ATF3) and its downstream target, proliferating cell nuclear antigen (PCNA). The evidence that IRF7/ATF3-double-TG (DTG) and IRF7/ATF3-double-KO (DKO) mice abolished the regulatory effects exhibited by the IRF7-TG and IRF7-KO mice, respectively, validated the underlying molecular events of IRF7-ATF3 interaction.
These findings demonstrated that IRF7 modulated VSMC proliferation and neointima formation by interacting with ATF3, thereby inhibiting the ATF3-mediated induction of PCNA transcription. The results of this study indicate that IRF7 is a novel modulator of neointima formation and VSMC proliferation and may represent a promising target for vascular disease therapy.
干扰素调节因子7(IRF7)是干扰素调节因子家族的成员,在先天免疫和免疫细胞分化中发挥重要作用。然而,IRF7在新生内膜形成中的作用目前尚不清楚。
在体内颈动脉损伤后以及体外血小板衍生生长因子-BB(PDGF-BB)刺激后,血管平滑肌细胞(VSMC)中IRF7表达显著降低。与非转基因(NTG)对照相比,平滑肌细胞特异性IRF7转基因(IRF7-TG)小鼠在颈动脉损伤后新生内膜形成和VSMC增殖减少,而IRF7的整体敲除(IRF7-KO)则产生相反的效果。值得注意的是,成功构建了一种新型的IRF7-KO大鼠品系,并基于球囊损伤诱导的血管病变模型用于进一步证实IRF7缺失对内膜增生加速的影响。机制上,IRF7对颈动脉增厚和VSMC增殖标志物表达的抑制作用依赖于IRF7与激活转录因子3(ATF3)及其下游靶点增殖细胞核抗原(PCNA)的相互作用。IRF7/ATF3双转基因(DTG)和IRF7/ATF3双敲除(DKO)小鼠分别消除了IRF7-TG和IRF7-KO小鼠所表现出的调节作用,这一证据验证了IRF7-ATF3相互作用的潜在分子事件。
这些发现表明,IRF7通过与ATF3相互作用调节VSMC增殖和新生内膜形成,从而抑制ATF3介导的PCNA转录诱导。本研究结果表明,IRF7是新生内膜形成和VSMC增殖的新型调节因子,可能是血管疾病治疗的一个有前景的靶点。