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Journal of Molecular Medicine

, Volume 96, Issue 6, pp 575–583 | Cite as

Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation

  • Akiko Eguchi
  • Yukinori Koyama
  • Alexander Wree
  • Casey D. Johnson
  • Ryota Nakamura
  • Davide Povero
  • David Kneiber
  • Masahiko Tameda
  • Patricia Contreras
  • Al Spada
  • Ariel E. Feldstein
Original Article

Abstract

Development of portal hypertension (PHT) is a central prognostic factor in patients with cirrhosis. Circulating microparticles (MPs) are released by hepatocytes in a caspase-dependent manner, are increased in circulation of patients with cirrhosis, and contribute to PHT via induction of impaired vasoconstrictor responses. Here, we tested the hypothesis that emricasan, a pan-caspase inhibitor, ameliorates PHT and reduction in release of MPs. We used a short-term and long-term protocol following common bile-duct ligation (BDL) in C57BL/6 mice (10 and 20 days, respectively). Mice were treated daily via intraperitoneal injection with 10 mg/kg/day of emricasan or placebo. Circulating MP levels were analyzed using flow cytometry and function via ex vivo angiogenesis assays. In contrast to BDL-placebo group, nearly all BDL-emricasan-treated mice survived after long-term BDL. Assessment of portal pressure showed a significant increase in BDL-placebo mice compared to sham-placebo mice. In contrast, BDL-emricasan mice had significantly lower levels of portal pressure compared to BDL-placebo mice. Although emricasan treatment resulted in a decrease in fibrosis, the changes did not reach statistical significance, suggesting that the effects on PHT are at least in part independent of the anti-fibrotic effects of the drug. Following short-term BDL, hepatocellular cell death as well as liver fibrosis had improved and circulating MPs were significantly reduced in BDL-emricasan mice compared to BDL-placebo. Circulating MPs from BDL-placebo mice induced endothelial cell activation, and this was significantly reduced in MPs from BDL-emricasan mice. Our results indicate that emricasan treatment improves survival and PHT in a murine model of long-term BDL. Emricasan is a promising agent for the treatment of PHT.

Key message

  • Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension induced by long-term bile-duct ligation (BDL) in mice

  • Emricasan reduces liver damage, hepatocyte death, and fibrosis, following short-term BDL in mice, and these changes are associated with a decrease in circulating microparticle (MPs)

  • Circulating MPs from BDL-placebo but not from BDL-emiricasan-treated mice activate endothelial cells ex vivo

Keywords

Portal hypertension Cirrhosis Pan-caspase inhibitor Extracellular vesicles 

Abbreviations

PHT

Portal hypertension

BDL

Bile-duct ligation

MP

Microparticle

Notes

Acknowledgements

UCSD Neuroscience Core for microscopy is supported by a grant NS047101.

Funding

This work was funded by NIH grants U01 AA022489 and Conatus Pharmaceuticals.

Compliance with ethical standards

Conflict of interest

The authors state no conflict of interest, except Al Spada and Patricia Contreras who are employees of Conatus Pharmaceuticals.

Supplementary material

109_2018_1642_MOESM1_ESM.docx (5.7 mb)
ESM 1 (DOCX 5800 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Akiko Eguchi
    • 1
  • Yukinori Koyama
    • 2
  • Alexander Wree
    • 1
  • Casey D. Johnson
    • 1
  • Ryota Nakamura
    • 1
  • Davide Povero
    • 1
  • David Kneiber
    • 1
  • Masahiko Tameda
    • 1
  • Patricia Contreras
    • 3
  • Al Spada
    • 3
  • Ariel E. Feldstein
    • 1
  1. 1.Department of PediatricsUniversity of California – San DiegoLa JollaUSA
  2. 2.School of MedicineUniversity of California – San DiegoLa JollaUSA
  3. 3.Conatus Pharmaceuticals Inc.San DiegoUSA

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