Pan Jinyu, Lu Lu, Wang Xuyang, Liu Dian, Tian Jingjing, Liu Hui, Zhang Mingjun, Xu Fengqin, An Fengshuang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, No, 107 WenHuaXi Road, Jinan, Shandong, CN 250012, China.
Jinan No. 4 People's Hospital, No, 50, Shifan Road, Jinan, Shandong, CN 250031, China.
Biochem Biophys Res Commun. 2018 Feb 26;497(1):401-409. doi: 10.1016/j.bbrc.2018.02.094. Epub 2018 Feb 12.
Atherosclerosis (AS) is a common pathological basis of various cardiovascular and cerebrovascular diseases. Plaque formation is initiated and triggered by vascular smooth musclecells (VSMCs) migration in vascular wall, which gradually aggravates atherosclerosis progression. Absent in melanoma 2 (AIM2), a member of HIN-200 family, plays an important role in activating inflammasome. However, the role of AIM2 in atherosclerotic plaque progression outside of the inflammasome has not yet been reported.
The potential effect and the underlying mechanism of AIM2 were investigated in apoliporotein E-deficient (ApoE-/-) mice. Murine AIM2 lentivirus, shRNA-AIM2 lentivirus and null lentivirus were constructed and injected intravenously into ApoE-/- mice, which were fed on a high fat diet. The specific mechanism of AIM2 in vascular smooth cells (VSMCs) was explored in vitro.
Results showed the aortic atherosclerotic lesion area was larger with AIM2 over-expression, and the number of smooth muscle cells was enhanced in line with the increased AIM2 levels. AIM2 overexpression also induced the increasing expression of MMP2. In vitro studies revealed that different levels of ox-LDL increased AIM2 expression in a time-dependent manner. Transwell showed that AIM2 mediated migration in VSMCs. The expression of AIM2 can be inhibited when the ROS inhibitor was used. Additionally, the overexpression and inhibition of AIM2 significantly affects HG-induced migration and TGF-β/SMAD signaling pathway in VSMCs.
Thus, we demonstrated that AIM2 could promote the progression of atherosclerotic plaque by increasing migration in VSMCs.
动脉粥样硬化（AS）是各种心脑血管疾病常见的病理基础。斑块形成始于并由血管壁中的血管平滑肌细胞（VSMC）迁移触发，这会逐渐加剧动脉粥样硬化的进展。黑色素瘤缺乏因子2（AIM2）是HIN-200家族的成员，在激活炎性小体中起重要作用。然而，AIM2在炎性小体之外的动脉粥样硬化斑块进展中的作用尚未见报道。
在载脂蛋白E缺陷（ApoE-/-）小鼠中研究AIM2的潜在作用及其潜在机制。构建小鼠AIM2慢病毒、shRNA-AIM2慢病毒和空慢病毒，并静脉注射到喂食高脂饮食的ApoE-/-小鼠体内。在体外探索AIM2在血管平滑肌细胞（VSMC）中的具体机制。
结果显示，随着AIM2过表达，主动脉粥样硬化病变面积增大，平滑肌细胞数量随AIM2水平升高而增加。AIM2过表达还诱导MMP2表达增加。体外研究表明，不同水平的氧化型低密度脂蛋白（ox-LDL）以时间依赖性方式增加AIM2表达。Transwell实验表明AIM2介导VSMC迁移。使用活性氧（ROS）抑制剂时可抑制AIM2表达。此外，AIM2的过表达和抑制显著影响高糖（HG）诱导的VSMC迁移以及转化生长因子-β（TGF-β）/SMAD信号通路。
因此，我们证明AIM2可通过增加VSMC迁移促进动脉粥样硬化斑块进展。
