The role of endothelin in the pathogenesis of vasculopathy associated with systemic sclerosis

内皮素在系统性硬化症相关血管病变发病机制中的作用

• 批准号: 23791256
• 负责人: ASANO Yoshihide
• 金额: $ 2.66万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23791256/
• 关键词: 全身性強皮症; 血管障害; Fli1; エンドセリン; ボセンタン; 創傷治癒; 国際情報交流 アメリカ合衆国

Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by initial vascular injuries and resultant fibrosis of skin and certain internal organs. Although the pathogenesis of SSc still remains unknown, recent studies have demonstrated that endothelins play a crucial role in the development of vasculopathy and fibrosis associated with SSc. Consistently, we recently showed that Fli1 deficiency is closely linked to the activation of fibroblasts and endothelial cells in SSc and a dual endothelin receptor antagonist, bosentan, reverses the pro-fibrotic phenotype of SSc dermal fibroblasts by increasing the transcriptional activity of Fli1. Based on these findings, we herein investigated the impact of bosentan on SSc vasculopathy using endothelia cell-specific Fli1 knockout mice, which mimic the morphological and functional abnormalities of SSc vasculopathy. A series of studies revealed that bosentan reverses Fli1 deficiency-dependent vasculopathy in these mice by increasing transcriptional activity of Fli1, suggesting that a similar mechanism potentially underpins the clinical efficacy of bosentan for SSc vasculopathy.

系统性硬化症(SSC)是一种多系统自身免疫性疾病，其特征是最初的血管损伤和由此导致的皮肤和某些内部器官的纤维化。尽管SSc的发病机制尚不清楚，但最近的研究表明，内皮素在SSC相关血管病变和纤维化的发生发展中起着至关重要的作用。我们最近一致地发现，FLI1缺乏与SSC成纤维细胞和内皮细胞的激活密切相关，并且双重内皮素受体拮抗剂波生坦通过增加FLI1的转录活性来逆转SSC真皮成纤维细胞的促纤维化表型。基于这些发现，我们在此利用内皮细胞特异性的FLI1基因敲除小鼠，模拟SSC血管病变的形态和功能异常，研究了波生坦对SSC血管病变的影响。一系列研究表明，波生坦通过增加FLI1的转录活性来逆转这些小鼠的FLI1缺乏性血管病变，这表明类似的机制可能支持波生坦治疗SSc血管病变的临床疗效。

项目成果

Bosentan reverses the profibrotic phenotype of systemic sclerosis dermal fibroblasts through increasing the DNA binding ability of transcription factor Fli1

波生坦通过增加转录因子 Fli1 的 DNA 结合能力来逆转系统性硬化症真皮成纤维细胞的促纤维化表型

• 发表时间: 2011
• 作者: Akamata K;Asano Y;Sato S
• 通讯作者: Sato S

The mechanism of impaired wound healing in animal models with increased vascular senescence

血管衰老增加的动物模型中伤口愈合受损的机制

• 发表时间: 2011
• 作者: Yoshihide Asano;Maria Trojanowska;Shinichi Sato.
• 通讯作者: Shinichi Sato.