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

• Project/Area Number: 23791256
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: The University of Tokyo
• Principal Investigator: ASANO Yoshihide 東京大学, 医学部附属病院, 講師 (60313029)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 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

Research Abstract

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.

Research Products

• [Journal Article] Decreased cathepsin V expression due to Fli1 deficiency contributes to the development of dermal fibrosis and proliferative vasculopathy in systemic sclerosis (2013)
  • Author(s): Noda S, Asano Y, Takahashi T, Akamata K, Aozasa N, Taniguchi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S
  • Journal Title: Rheumatology (Oxford) Volume: 52 Pages: 790-9
  • Peer Reviewed
• [Journal Article] A possible contribution of altered cathepsin B expression to the development of skin sclerosis and vasculopathy in systemic sclerosis (2012)
  • Author(s): Noda S, Asano Y, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] A possible contribution of altered cathepsin B expression to the development of skin sclerosis and vasculopathy in systemic sclerosis. (2012)
  • Author(s): Noda S, Asano Y, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Effects of bosentan on nondigital ulcers in patients with systemic sclerosis. (2012)
  • Author(s): Taniguchi T, Asano Y, Hatano M, Tamaki Z, Tomita M, Kawashima T, Miyazaki M, Sumida H, Akamata K, Takahashi T, Ichimura Y, Toyama T, Sugita M, Noda S, Yao A, Kinugawa K, Sato S.
  • Journal Title: Br J Dermatol. Volume: 166 Pages: 417-21
  • Peer Reviewed
• [Journal Article] Significant attenuation of macrovascular involvement by bosentan in a patient with diffuse cutaneous systemic sclerosis with multiple digital ulcers and gangrene. (2011)
  • Author(s): Ichimura Y, Asano Y, Hatano M, Tamaki Z, Takekoshi T, Kogure A, Tomita M, Kawashima T, Miyazaki M, Taniguchi T, Takahashi T, Mitsui H, Sugaya M, Yao A, Kinugawa K, Sato S.
  • Journal Title: Mod Rheumatol. Volume: 21 Pages: 548-52
  • NAID: 10030205881
  • Peer Reviewed
• [Presentation] The impact of Fli1 deficiency on the pathogenesis of systemic sclerosis (2012)
  • Author(s): Asano Y
  • Organizer: The 37th annual meeting of JSID
  • Place of Presentation: 沖縄
  • Year and Date: 2012-12-08
• [Presentation] 強皮症の基礎と臨床 (2012)
  • Author(s): 浅野善英
  • Organizer: 第61回東海膠原病研究会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-07-14
• [Presentation] 強皮症の血管障害 (2012)
  • Author(s): 浅野善英
  • Organizer: 日本皮膚科学会総会
  • Place of Presentation: 京都
  • Year and Date: 2012-06-02
• [Presentation] 強皮症の血管障害 (2012)
  • Author(s): 浅野善英
  • Organizer: 日本皮膚科学会総会
  • Place of Presentation: 京都国際会議場
  • Invited
• [Presentation] Themechanism of impaired wound healing in animal models with increased vascular senescence (2011)
  • Author(s): Asano Y, Trojanowska M, Sato S
  • Organizer: The 36th annual meeting of the JSID
  • Place of Presentation: Kyoto, JAPAN
  • Year and Date: 2011-12-08
• [Presentation] Bosentan reverses the profibrotic phenotype of systemic sclerosis dermal fibroblasts through increasing the DNA binding ability of transcription factor Fli1 (2011)
  • Author(s): Akamata K, Asano Y, Sato S
  • Organizer: The75th Annual Scientific Meeting ofAmerican College of Rheumatology
  • Place of Presentation: Chicago, USA
  • Year and Date: 2011-11-08
• [Presentation] The mechanism of impaired wound healing in animal models with increased vascular senescence (2011)
  • Author(s): Yoshihide Asano, Maria Trojanowska, Shinichi Sato.
  • Organizer: The 36th annual meeting of the JSID
  • Place of Presentation: Kyoto, JAPAN
• [Presentation] Bosentan reverses the profibrotic phenotype of systemic sclerosis dermal fibroblasts through increasing the DNA binding ability of transcription factor Fli1 (2011)
  • Author(s): Kaname Akamata, Yoshihide Asano, Shinichi Sato.
  • Organizer: 2011 The 75th Annual Scientific Meeting of American College of Rheumatology
  • Place of Presentation: Chicago, USA