AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling

Xingwen Da, Ziyan Li, Xiaofan Huang, Zuhan He, Yubing Yu, Tongtong Tian, Chengqi Xu (), Yufeng Yao () and Qing K. Wang ()
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Xingwen Da: Huazhong University of Science and Technology
Ziyan Li: Huazhong University of Science and Technology
Xiaofan Huang: Tongji Medical College, Huazhong University of Science and Technology
Zuhan He: Huazhong University of Science and Technology
Yubing Yu: Huazhong University of Science and Technology
Tongtong Tian: Huazhong University of Science and Technology
Chengqi Xu: Huazhong University of Science and Technology
Yufeng Yao: Huazhong University of Science and Technology
Qing K. Wang: Huazhong University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37809-x

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