Deletion of Fam172a accelerates advanced atherosclerosis and induces plaque instability

Abstract

Background and aimsVascular 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. MethodsFam172a−/− 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. ResultsCompared 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. ConclusionsOur 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.