PDF(Pubmed)
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.
摘要：
胸主动脉瘤（TAA）是胸主动脉的局部或弥漫性扩张，每年都会导致许多人突然死亡。然而,没有有效的药物治疗。这里,我们显示AGGF1在三种不同的小鼠模型中有效阻断TAA相关的动脉炎症和重塑（患有主动脉横缩窄的小鼠，Fbn1C1041G/+小鼠，和β-氨基丙腈处理的小鼠)。三种模型和人TAA患者的升主动脉中AGGF1表达降低。Aggf1+/-小鼠和血管平滑肌细胞(VSMC)特异性Aggf1smcKO敲除小鼠显示出加重的TAA表型。机械上,AGGF1增强其受体整联蛋白α7与潜伏期相关肽（LAP）-TGF-β1之间的相互作用，阻断LAP-TGF-β1的裂解形成成熟的TGF-β1，并抑制Smad2/3和ERK1/2在VSMC中的磷酸化。吡非尼酮,特发性肺纤维化的治疗药物,在野生型小鼠中抑制TAA相关的血管炎症和重塑，但在Aggf1+/-小鼠中没有。总之,我们确定了一种创新的AGGF1蛋白治疗策略来阻断TAA相关的血管炎症和重塑，并显示TGF-β抑制疗法的功效需要AGGF1。
