Aims

To address the roles of SHP2 in regulating angiotensin II (Ang II) induced abdominal aortic aneurysm (AAA) and the potential molecular mechanisms.

Main methods

AAA model was established in apolipoprotein E-deficient (apoE^−/−) mice infused with Ang II. Suprarenal aortic luminal diameters were ultrasonically measured to determine the presentation of AAA in mice. The inflammatory and immunosuppressive factors in serum were detected by ELISA. AAA lesion size, positive macrophages and elastic laminae degradation were examined by histological analysis. Myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry after magnetic bead sorting. Bioinformatics analysis was applied to screen the crucial genes related the progression of AAA.

Key findings

Treatment with PHPS1 (SHP2 inhibitor) significantly decreased the vascular diameter of AAA. Histological analysis showed that PHPS1 obviously reduced the Masson positive area, macrophages positive area, as well as the damage rate of elastic laminae. Moreover, PHPS1 suppressed the expression of INF-γ, TNF-α and MMPs, as well as elevated IL-10 and arginase-1 expression. Additionally, PHPS1 enhanced the expression of granulocytic MDSCs (G-MDSCs). By consulting with bioinformatics, STAT3 was selected. In G-MDSCs, PHPS1 stimulation obviously increased the phosphorylation level of STAT3, as well as elevated the protein expression of C/EBPβ and arginase-1. However, the above phenomena can be blocked after Stattic (STAT3 inhibitor) treatment.

Significance

SHP2 may affect the AAA progression by interfering with expansion and function of MDSCs to regulate the body immunity, which might afford a novel direction for the treatment of patients with AAA.

中文翻译：

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SHP2的特异性抑制通过增强MDSC的免疫抑制功能而抑制了小鼠腹主动脉瘤的形成

目的

为了解决SHP2在调节血管紧张素II（Ang II）诱导的腹主动脉瘤（AAA）中的作用及其潜在的分子机制。

主要方法

在输注Ang II的载脂蛋白E缺陷（apoE ^-/-）小鼠中建立AAA模型。超声测量肾上动脉主动脉腔直径，以确定在小鼠中AAA的表现。ELISA法检测血清中的炎症和免疫抑制因子。通过组织学分析检查了AAA病变的大小，阳性巨噬细胞和弹性薄片的降解。磁珠分选后，通过流式细胞仪测量了骨髓来源的抑制细胞（MDSC）。应用生物信息学分析来筛选与AAA进展相关的关键基因。

主要发现

用PHPS1（SHP2抑制剂）治疗可显着降低AAA的血管直径。组织学分析表明，PHPS1明显减少了Masson阳性区域，巨噬细胞阳性区域以及弹性层的损伤率。此外，PHPS1抑制INF-γ，TNF-α和MMP的表达，以及IL-10和精氨酸酶1的表达升高。此外，PHPS1增强了粒细胞MDSC（G-MDSC）的表达。通过咨询生物信息学，选择了STAT3。在G-MDSCs中，PHPS1刺激明显增加了STAT3的磷酸化水平，并提高了C /EBPβ和精氨酸酶-1的蛋白表达。但是，上述现象可以在Stattic（STAT3抑制剂）治疗后被阻断。

意义

SHP2可能通过干扰MDSCs的扩增和功能来调节机体免疫力，从而影响AAA进程，这可能为AAA患者的治疗提供新的方向。