Journal Article

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

Yao, Yufeng, Xu, Chengqi, Yu, Yubing, He, Zuhan, Wang, Qing K., Li, Ziyan, Huang, Xiaofan, Tian, Tongtong, Da, Xingwen

2023

Overview

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 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 Aggf1 smcKO 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. Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/44 / 13/51 / 13/95 / 38/1 / 38/109 / 38/22 / 38/23 / 38/44 / 38/77 / 38/88 / 38/90 / 631/80/86/2368 / 64/110 / 64/60 / 692/420/256/2515 / 692/699/75/593/1287 / 96/1 / 96/109 / Angiogenic Proteins - genetics / Animal models / Animals / Aorta / Aortic Aneurysm, Thoracic - genetics / Aortic aneurysms / Extracellular signal-regulated kinase / Fatalities / Fibrosis / Humanities and Social Sciences / Humans / Inflammation / Inflammation - metabolism / Latency / Lung diseases / MAP Kinase Signaling System / Maturation / Medical innovations / Mice / Mice, Knockout / multidisciplinary / Myocytes, Smooth Muscle - metabolism / Phenotypes / Phosphorylation / Proteins / Science / Science (multidisciplinary) / Signaling / Smad2 protein / Smooth muscle / Therapy / Thorax / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b / Transforming growth factor-b1