Spatiotemporal ATF3 Expression Determines VSMC Fate in Abdominal Aortic Aneurysm

被引：4

作者：

Wen, Ying ^{[1
]}

Liu, Yingying ^{[1
]}

Li, Qiang ^{[5
]}

Tan, Jinlin ^{[1
]}

Fu, Xing ^{[1
]}

Liang, Yiwen ^{[8
]}

Tuo, Yonghua ^{[6
]}

Liu, Luhao ^{[7
]}

Zhou, Xueqiong ^{[9
]}

LiuFu, Dongkai ^{[1
]}

Fan, Xuejiao ^{[1
]}

Chen, Chaofei ^{[1
]}

Chen, Zheng ^{[7
]}

Wang, Zhouping ^{[2
]}

Fan, Shunyang ^{[3
]}

Liu, Renjing ^{[4
]}

Pan, Lei ^{[10
]}

Zhang, Yuan ^{[1
]}

Tang, Wai Ho ^{[1
,3
,11
]}

机构：

[1] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Inst Pediat, Guangzhou, Peoples R China

[2] Guangzhou Med Univ, Guangzhou Women & Childrens Med Ctr, Dept Cardiol, Guangzhou, Peoples R China

[3] Zhengzhou Univ, Affiliated Hosp 3, Heart Ctr, Zhengzhou, Peoples R China

[4] Victor Chang Cardiac Res Inst, Sydney, Australia

[5] Guangzhou Med Univ, Affiliated Hosp 2, Dept Vasc Surg, Guangzhou, Peoples R China

[6] Guangzhou Med Univ, Affiliated Hosp 2, Dept Neurosurg, Guangzhou, Peoples R China

[7] Guangzhou Med Univ, Affiliated Hosp 2, Dept Organ Transplantat, Guangzhou, Peoples R China

[8] Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Hlth, Guangzhou, Peoples R China

[9] Southern Med Univ, Sch Publ Hlth, Dept Occupat Hlth & Occupat Med, Guangzhou, Peoples R China

[10] Chinese Acad Sci, Inst Pasteur Shanghai, Ctr Microbes Dev & Hlth, Key Lab Mol Virol & Immunol, Shanghai, Peoples R China

[11] Hong Kong Metropolitan Univ, Sch Nursing & Hlth Studies, Kowloon, Hong Kong, Peoples R China

来源：

CIRCULATION RESEARCH | 2024年 / 134卷 / 11期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

abdominal aortic aneurysm; apoptosis; phenotypic switch; prognostic marker; vascular smooth muscle cell; CELLS;

D O I：

10.1161/CIRCRESAHA.124.324323

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND:Abdominal aortic aneurysm (AAA) is a catastrophic disease with little effective therapy, likely due to the limited understanding of the mechanisms underlying AAA development and progression. ATF3 (activating transcription factor 3) has been increasingly recognized as a key regulator of cardiovascular diseases. However, the role of ATF3 in AAA development and progression remains elusive.METHODS:Genome-wide RNA sequencing analysis was performed on the aorta isolated from saline or Ang II (angiotensin II)-induced AAA mice, and ATF3 was identified as the potential key gene for AAA development. To examine the role of ATF3 in AAA development, vascular smooth muscle cell-specific ATF3 knockdown or overexpressed mice by recombinant adeno-associated virus serotype 9 vectors carrying ATF3, or shRNA-ATF3 with SM22 alpha (smooth muscle protein 22-alpha) promoter were used in Ang II-induced AAA mice. In human and murine vascular smooth muscle cells, gain or loss of function experiments were performed to investigate the role of ATF3 in vascular smooth muscle cell proliferation and apoptosis.RESULTS:In both Ang II-induced AAA mice and patients with AAA, the expression of ATF3 was reduced in aneurysm tissues but increased in aortic lesion tissues. The deficiency of ATF3 in vascular smooth muscle cell promoted AAA formation in Ang II-induced AAA mice. PDGFRB (platelet-derived growth factor receptor beta) was identified as the target of ATF3, which mediated vascular smooth muscle cell proliferation in response to TNF-alpha (tumor necrosis factor-alpha) at the early stage of AAA. ATF3 suppressed the mitochondria-dependent apoptosis at the advanced stage by upregulating its direct target BCL2. Our chromatin immunoprecipitation results also demonstrated that the recruitment of NF kappa B1 and P300/BAF/H3K27ac complex to the ATF3 promoter induces ATF3 transcription via enhancer activation. NFKB1 inhibitor (andrographolide) inhibits the expression of ATF3 by blocking the recruiters NFKB1 and ATF3-enhancer to the ATF3-promoter region, ultimately leading to AAA development.CONCLUSIONS:Our results demonstrate a previously unrecognized role of ATF3 in AAA development and progression, and ATF3 may serve as a novel therapeutic and prognostic marker for AAA.

引用

页码：1495 / 1511

页数：17