ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 1710

Endothelin-1 Is a Downstream Mediator of Profibrotic Effects by Transforming Growth Factor-β1 in Systemic Sclerosis Skin Fibroblasts

Tomoaki Higuchi1, Yasushi Kawaguchi1, Akiko Tochimoto1, Yuko Ota2, Yasuhiro Katsumata1, Takahisa Gono1, Masanori Hanaoka1, Yuko Okamoto1, Hidenaga Kawasumi1 and Hisashi Yamanaka3, 1Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, 210-22 Kawada-Cha Shinjuku-Ku, Tokyo Women's Medical University, Tokyo, Japan, 3Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Fibroblasts, fibrosis and systemic sclerosis

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by excess collagen deposition, vascular changes and production of autoantibodies that affects multiple organs. Transforming growth factorβ1 (TGF-β1), that promotes collagen synthesis, extracellular matrix (ECM) remodeling and myofibroblast differentiation, is thought to play a key role in the pathogenesis of SSc. The vasoconstrictive peptide endothelin-1 (ET-1) is also known as potent fibrotic factors. ET-1 binds to two distinct subtype of G protein coupled receptors, ET receptor A (ETRA) and ET receptor B (ETRB). The fibrotic functions of each ET receptor remain unclear partly because the distribution and expression of ET receptors differs according to the disease situations, the respective organs or the cell types. The aim of our study was to examine the effects of TGF-β1 on the fibrogenic phenotype of SSc skin fibroblasts through ET-1 production and to clarify how the signal transduction through TGF-β1 is associated with upregulation of ET-1.

Methods

Human SSc skin fibroblasts (SSc fibroblasts) were obtained from 5 SSc patients. Recombinant TGF-β1, recombinant ET-1, SIS3 as an inhibitor of Smad3 phosphorylation, SP600125 as an inhibitor of c-JUN N-terminal kinase (JNK), BQ123 as a selective  ETRA antagonist, BQ788 as a selective ETRB antagonist and bosentan as a dual ETRA/ETRB receptor antagonist were used in this study. SSc fibroblasts were incubated with TGF-β1 in the presence of SIS3 or SP600125. In addition, the effects of BQ123, BQ788 or bosentan were explored. The expression of ET-1, CTGF and type Ⅰ collagen was evaluated using ELISA and real time RT-PCR. ETRA and ETRB expressions were assessed by immunohistochemistry and fluorescence activated cell sorting (FACS) analysis. 

Results

Both ETRA and ETRB were expressed in SSc fibroblasts as detected by immunohistochemistry. TGF-β1 increased ET-1 in the levels of mRNA and protein and this increase in ET-1 was suppressed by either SIS3 or SP600125. Upregulation of COL1A1 and CTGF by TGF-β1 were reduced by either ETRA or ETRB antagonist, and the effects were enhanced by dual ETRA/ETRB antagonist. 

Conclusion

We herein revealed that TGF-β1 produced ET-1 through both Smad and JNK cascade and dual ETRA/ETRB antagonist contributed to diminishing COL1A1 and CTGF mRNA in fibroblasts. These findings suggest that the fibrogenic effects by TGF-b1 may in part be explained by the autocrine stimulation of ET-1. The dual ETRA/ETRB might be a novel therapeutic strategy for the SSc skin fibrosis.


Disclosure:

T. Higuchi,
None;

Y. Kawaguchi,
None;

A. Tochimoto,
None;

Y. Ota,
None;

Y. Katsumata,
None;

T. Gono,
None;

M. Hanaoka,
None;

Y. Okamoto,
None;

H. Kawasumi,
None;

H. Yamanaka,
None.

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/endothelin-1-is-a-downstream-mediator-of-profibrotic-effects-by-transforming-growth-factor-%ce%b21-in-systemic-sclerosis-skin-fibroblasts/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology