| First Author | Da X | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 2265 |
| PubMed ID | 37081014 | Mgi Jnum | J:335321 |
| Mgi Id | MGI:7465761 | Doi | 10.1038/s41467-023-37809-x |
| Citation | Da X, et al. (2023) AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin alpha7-mediated inhibition of TGF-beta1 maturation and ERK1/2 signaling. Nat Commun 14(1):2265 |
| abstractText | 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, Fbn1(C1041G/+) mice, and beta-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 Aggf1(smcKO) knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin alpha7 and latency-associated peptide (LAP)-TGF-beta1, blocks the cleavage of LAP-TGF-beta1 to form mature TGF-beta1, 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-beta inhibition therapies require AGGF1. |
