AIP1维持血管平滑肌细胞稳态并影响腹主动脉瘤形成的机制研究

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease, the phenotypic transition of vascular smooth muscle cells (VSMC) exists at the early stage of AAA formation, but the underlying mechanism is not clear. GWAS analysis showed that mutation of AIP1 was associated with AAA formation. Our preliminary data showed the protein levels of AIP1 and VSMC contractile markers were decreased during AAA formation, AIP1 knockdown in VSMC inhibited the contractile markers expression. Moreover, AIP1 modulated the expression of FOXO3 and myocardin, and FOXO3 played a protective role in the expression of VSMC contractile markers. Based on these we hypothesize that AIP1 can inhibit AAA formation through maintaining VSMC contractile function, which depends on FOXO3 and myocardin. Through this project, we expect to uncover the effect of AIP1 on VSMC contractile function and AAA formation, and hope to find out a new target for AAA therapy.

腹主动脉瘤（AAA）是老年人高发的心血管疾病，血管平滑肌细胞（VSMC）收缩功能下降是AAA形成早期的重要事件，但其调控机制尚不清楚。GWAS研究表明AIP1突变与AAA形成具有相关性，但AIP1是否参与AAA形成有待进一步研究。我们发现在AAA形成过程中AIP1及VSMC收缩蛋白表达均明显下降，敲低VSMC中的AIP1可降低收缩蛋白的表达；进一步研究发现AIP1调控FOXO3及myocardin的表达；此外，敲低FOXO3可负向调控myocardin并抑制VSMC收缩蛋白的表达。因此，我们提出假说：AIP1通过调控VSMC收缩功能影响AAA的形成，具体机制为调控FOXO3及myocardin的表达。该项目对阐明AIP1在VSMC收缩表型调控及其在AAA形成中的作用机制有着重要意义，为预防及治疗AAA提供新的靶点和思路。

血管平滑肌细胞（VSMC）表型转化是腹主动脉瘤（AAA）形成早期的重要事件。本项目主要研究AIP1在AAA发生发展中的作用机制，我们研究发现，AIP1缺陷可促进弹力酶及磷酸钙诱导的AAA形成，并且抑制VSMC的收缩功能；机制研究表明AIP1可通过14-3-3β/α调控FOXO3的表达，提示AIP1可能是AAA治疗的潜在靶点。此外，我们发现AIP1缺失抑制内脏脂肪细胞摄取葡萄糖及促进其发生胰岛素抵抗，并且AIP1的表达与T2D的临床指标HOMA-IR及WHR呈负相关。具体机制为AIP1缺失的内脏脂肪细胞可激活JNK及p38 MAPK/ERK信号通路，促进TNF-α的产生，提示AIP1可作为肥胖合并二型糖尿病的预测指标。项目共发表带第一标注的SCI论文1篇，IF＞5。