Deletion of Fam172a accelerates advanced atherosclerosis and induces plaque instability

Ming-Yun Chen; Jiang-Feng Ke; Zhi-Hui Zhang; Mei-Fang Li; Jun-Wei Wang; Jun-Xi Lu; Pei-Pei Xu; Xiao-Tian Xia; Ming-Gao Guo; Lian-Xi Li

doi:10.1016/j.atherosclerosis.2021.08.023

Deletion of Fam172a accelerates advanced atherosclerosis and induces plaque instability

Atherosclerosis. 2021 Sep:333:39-47. doi: 10.1016/j.atherosclerosis.2021.08.023. Epub 2021 Aug 12.

Authors

Ming-Yun Chen¹, Jiang-Feng Ke², Zhi-Hui Zhang², Mei-Fang Li³, Jun-Wei Wang², Jun-Xi Lu², Pei-Pei Xu⁴, Xiao-Tian Xia⁴, Ming-Gao Guo⁴, Lian-Xi Li⁵

Affiliations

¹ Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600 Yishan Road, 200233, Shanghai, China; Department of Endocrinology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian, China.
² Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600 Yishan Road, 200233, Shanghai, China.
³ Department of Emergency, Shanghai Jiao Tong University Affiliated Sixth People's Hospital; 600 Yishan Road, Shanghai, 200233, China.
⁴ Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
⁵ Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, 600 Yishan Road, 200233, Shanghai, China. Electronic address: lilx@sjtu.edu.cn.

PMID: 34425526
DOI: 10.1016/j.atherosclerosis.2021.08.023

Abstract

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.

Keywords: Atherosclerosis; Fam172a; KLF4; Phenotypic switching; Plaque instability; Vascular smooth muscle cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis* / genetics
Cells, Cultured
Kruppel-Like Factor 4
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
Plaque, Atherosclerotic*