July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Involvement of caspase 7 in the excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy
Author Affiliations & Notes
  • Shigehito Tonomura
    Doshisha University, Kyotanabe, Kyoto, Japan
  • Naoki Okumura
    Doshisha University, Kyotanabe, Kyoto, Japan
  • Mako Endo
    Doshisha University, Kyotanabe, Kyoto, Japan
  • Makiko Nakahara
    Doshisha University, Kyotanabe, Kyoto, Japan
  • Theofilos Tourtas
    University of Erlangen-Nürnberg, Germany
  • Ursula Schlotzer-Schrehardt
    University of Erlangen-Nürnberg, Germany
  • Friedrich E Kruse
    University of Erlangen-Nürnberg, Germany
  • Noriko Koizumi
    Doshisha University, Kyotanabe, Kyoto, Japan
  • Footnotes
    Commercial Relationships   Shigehito Tonomura, None; Naoki Okumura, ActualEyes, Inc. (I), Doshisha University (F), Doshisha University (P), Kowa Company Ltd. (C), Senju Pharmaceutical Co.,Ltd. (P); Mako Endo, None; Makiko Nakahara, None; Theofilos Tourtas, None; Ursula Schlotzer-Schrehardt, None; Friedrich Kruse, None; Noriko Koizumi, ActualEyes, Inc. (I), Doshisha University (F), Doshisha University (P), Japan Innovative Therapeutics, Inc. (F), Kowa Company Ltd. (F), Kowa Company Ltd. (C), M’s Science Corporation (F), M’s Science Corporation (C), Senju Pharmaceutical Co.,Ltd. (F), Senju Pharmaceutical Co.,Ltd. (C), Senju Pharmaceutical Co.,Ltd. (R), Senju Pharmaceutical Co.,Ltd. (P)
  • Footnotes
    Support  Program for the Strategic Research Foundation at Private Universities from Japanese Ministry of Education, Culture, Sports, Science and Technology, JSPS KAKENHI Grant Numbers 16K11307 and 18K09464.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2176. doi:
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      Shigehito Tonomura, Naoki Okumura, Mako Endo, Makiko Nakahara, Theofilos Tourtas, Ursula Schlotzer-Schrehardt, Friedrich E Kruse, Noriko Koizumi; Involvement of caspase 7 in the excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2176.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We previously reported that the activation of transforming growth factor beta (TGF-β) signaling is involved in the excessive production of extracellular matrix (ECM) proteins in Fuchs endothelial corneal dystrophy (FECD). We also showed that activation of TGF-β signaling activated caspase 3 and induced corneal endothelial cell death. While caspase is known to play a key role in apoptosis, it has been suggested that inhibition of caspase suppresses ECM production in liver cells. The purpose of this present study was to investigate the involvement of caspases in ECM production in FECD.

Methods : After obtaining informed patient consent, corneal endothelial cells were isolated from Descemet’s membrane including corneal endothelium obtained from FECD patients during Descemet's membrane endothelial keratoplasty. The corneal endothelial cells were then cultured and immortalized as an FECD cell model (iFECD), and were then treated with TGF-β2 (10 ng/mL) to induce ECM production. iFECD was then treated with a pan-caspase inhibitor (emricasan), and the effect on ECM and epithelial-mesenchymal transition (EMT)-related molecules were evaluated by quantitative polymerase chain reaction (qPCR) and western blotting. siRNA was used to knockdown caspase 1, 3, 4, 7, 8, or 9, and the effect of the knockdown on TGF-β2-mediated induction of ECM and EMT-related molecules was evaluated.

Results : qPCR showed that emricasan significantly downregulated TGF-β2-mediated upregulation of FN1, COL1A1, SNAI1, and SNAI2 in iFECD (p<0.05). Consistently, western blotting showed that the TGF-β2-mediated upregulation of fibronectin and Snail1 were suppressed by emricasan, and that TGF-β2-mediated upregulation of fibronectin was not suppressed by the knockdown of caspase 1, 3, 4, 8, or 9 in iFECD. In contrast, knockdown of caspase 7 counteracted the upregulation of fibronectin and Snail1. Western blotting also showed that TGF-β2 treatment induced cleavage of caspase 7 in iFECD.

Conclusions : The findings of this study showed that caspase 7 activation is involved in excessive ECM production through activation of the TGF-βsignaling pathway in FECD. Further study regarding the role of caspase 7 might be beneficial for elucidating the pathogenesis of FECD.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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