Interferon regulatory factor 7 protects against vascular smooth muscle cell proliferation and neointima formation.
Interferon regulatory factor 7 protects against vascular smooth muscle cell proliferation and neointima formation.
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干扰素调节因子 7 可防止血管平滑肌细胞增殖和新内膜形成
DOI：
10.1161/jaha.114.001309
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发表时间：
2014-10-10
影响因子：
5.4
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Huang L;Zhang SM;Zhang P;Zhang XJ;Zhu LH;Chen K;Gao L;Zhang Y;Kong XJ;Tian S;Zhang XD;Li H
背景干扰素调节因子7（Interferon Regulatory Factor 7，IRF 7）是干扰素调节因子家族的成员之一，在天然免疫和免疫细胞分化中起重要作用。然而，IRF 7在新生内膜形成中的作用目前尚不清楚。方法和结果在体内颈动脉损伤和体外血小板衍生生长因子-BB（PDGF-BB）刺激后，在血管平滑肌细胞（VSMC）中观察到IRF 7表达显著降低。与非转基因（NTG）对照组相比，SMC特异性IRF 7转基因（IRF 7-TG）小鼠在颈动脉损伤后显示新生内膜形成和VSMC增殖减少，而IRF 7的整体敲除（IRF 7-KO）导致相反的效果。值得注意的是，成功产生了一种新的IRF 7-KO大鼠品系，并用于基于球囊损伤诱导的血管病变模型进一步证实IRF 7缺失对内膜增生加速的影响。从机制上讲，IRF 7抑制颈动脉增厚和VSMC增殖标志物的表达依赖于IRF 7与活化转录因子3（ATF 3）及其下游靶点增殖细胞核抗原（PCNA）的相互作用。IRF 7/ATF 3-double-TG（DTG）和IRF 7/ATF 3-double-KO（DKO）小鼠分别消除了IRF 7-TG和IRF 7-KO小鼠表现出的调节作用的证据验证了IRF 7-ATF 3相互作用的潜在分子事件。结论IRF 7通过与ATF 3相互作用，抑制ATF 3诱导的PCNA转录，从而调控VSMC增殖和内膜形成。这项研究的结果表明，IRF 7是一种新的调节新生内膜形成和VSMC增殖，并可能代表一个有前途的目标，血管疾病的治疗。
Background 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. Methods and Results 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. Conclusions 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.