AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling
发布时间：2023-10-19
点击次数：
- 论文类型：
- 期刊论文
- 论文编号：
- 2265
- 通讯作者：
- 徐承启
- 发表刊物：
- NATURE COMMUNICATIONS
- 收录刊物：
- SCI
- 所属单位：
- 华中科技大学生命科学与技术学院
- 学科门类：
- 理学
- 卷号：
- 14
- 期号：
- 1
- 页面范围：
- 2265
- DOI码：
- 10.1038/s41467-023-37809-x
- 发表时间：
- 2023-04-20
- 影响因子：
- 16.6
- 教研室：
- 人类基因组研究中心
- 摘要：
- Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1+/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1+/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.