Background and aims

Vascular smooth muscle cells (VSMCs) play a critical role in atherosclerosis. The family with sequence similarity 172, member A (FAM172A) is a novel protein and its role in atherosclerosis has not been explored so far. Therefore, our aim is to investigate whether FAM172A affects atheroprogression through VSMCs and its possible mechanism.

Methods

Fam172a^−/− mice were generated using CRISPR/Cas9 technology. Fam172a^−/− and Apoe^−/− double knockout (Fam172a^−/−/Apoe^−/−) mice and their littermates (Fam172a^+/+/Apoe^−/−) were fed with a Western diet for 18 weeks to induce advanced atherosclerotic lesions. The role and mechanism of Fam172a in phenotypic switching, proliferation and migration of VSMCs were investigated through in vivo and in vitro experiments.

Results

Compared with Fam172a^+/+/Apoe^−/− mice, Fam172a^−/−/Apoe^−/− mice showed increased atherosclerotic lesion size and plaque instability such as increased necrotic core area and decreased fiber deposition. Additionally, knockout of Fam172a promoted expression of CD68 and KLF4 and decreased expression of α-SMA and SM22α in atherosclerotic lesions. Furthermore, overexpression of Fam172a promoted Movas cells proliferation and migration, increased expression of α-SMA and SM22α and decreased expression of KLF4. Meanwhile, knockdown of Fam172a in Movas cells and deletion of Fam172a in VSMCs from Fam172a^−/−/Apoe^−/− mice showed opposite phenotypes. Similar phenotypes were also observed in human aortic smooth muscle cells.

Conclusions

Our results provide the first direct evidence that Fam172a has a protective role in advanced atherosclerosis by increasing atherosclerotic plaque stability and inhibiting transition of VSMCs from contractile to synthetic phenotype, which may be through KLF4-dependent pathway.

中文翻译：

---

Fam172a 的缺失加速晚期动脉粥样硬化并诱导斑块不稳定

背景和目标

血管平滑肌细胞 (VSMC) 在动脉粥样硬化中起关键作用。具有序列相似性 172 的家族成员 A (FAM172A) 是一种新型蛋白质，目前尚未探索其在动脉粥样硬化中的作用。因此，我们的目的是研究 FAM172A 是否通过 VSMC 影响动脉粥样硬化的进展及其可能的机制。

方法

Fam172a ^-/-小鼠是使用 CRISPR/Cas9 技术生成的。Fam172a ^-/-和Apoe ^-/-双基因敲除 ( Fam172a ^-/- / Apoe ^-/- ) 小鼠及其同窝小鼠 ( Fam172a ^+/+ / Apoe ^-/- ) 用西方饮食喂养 18 周以诱导晚期动脉粥样硬化病变。的作用和机理Fam172a在表型开关，增殖和血管平滑肌细胞迁移通过进行了研究体内和体外实验。

结果

与Fam172a ^+/+ / Apoe ^-/-小鼠相比，Fam172a ^-/- / Apoe ^-/-小鼠显示出增加的动脉粥样硬化病变大小和斑块不稳定性，例如增加的坏死核心面积和减少的纤维沉积。此外，敲除Fam172a 可促进动脉粥样硬化病变中 CD68 和 KLF4 的表达并降低 α-SMA 和 SM22α 的表达。此外，Fam172a 的过表达促进了 Movas 细胞的增殖和迁移，增加了 α-SMA 和 SM22α 的表达并降低了 KLF4 的表达。同时，Movas 细胞中 Fam172a 的敲低和来自Fam172a 的VSMC 中Fam172a 的缺失^-/-/ Apoe ^-/-小鼠表现出相反的表型。在人主动脉平滑肌细胞中也观察到类似的表型。

结论

我们的研究结果提供了第一个直接证据，即Fam172a通过增加动脉粥样硬化斑块的稳定性和抑制 VSMC 从收缩表型向合成表型的转变，在晚期动脉粥样硬化中具有保护作用，这可能是通过 KLF4 依赖性途径。