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

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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

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Abbreviations

PHT:

Portal hypertension

BDL:

Bile-duct ligation

MP:

Microparticle

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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.

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Authors and Affiliations

  1. Department of Pediatrics, University of California – San Diego, 9500 Gilman Drive, MC 0715, 9500 Gilman Drive, La Jolla, CA, USA

    Akiko Eguchi, Alexander Wree, Casey D. Johnson, Ryota Nakamura, Davide Povero, David Kneiber, Masahiko Tameda & Ariel E. Feldstein

  2. School of Medicine, University of California – San Diego, 9500 Gilman Drive, La Jolla, CA, USA

    Yukinori Koyama

  3. Conatus Pharmaceuticals Inc., San Diego, CA, USA

    Patricia Contreras & Al Spada

Authors
  1. Akiko Eguchi
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  2. Yukinori Koyama
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  3. Alexander Wree
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  4. Casey D. Johnson
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  5. Ryota Nakamura
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  6. Davide Povero
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  7. David Kneiber
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  8. Masahiko Tameda
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  9. Patricia Contreras
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  10. Al Spada
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  11. Ariel E. Feldstein
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Corresponding author

Correspondence to Ariel E. Feldstein.

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Conflict of interest

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

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Eguchi, A., Koyama, Y., Wree, A. et al. Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation. J Mol Med 96, 575–583 (2018). https://doi.org/10.1007/s00109-018-1642-9

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  • DOI: https://doi.org/10.1007/s00109-018-1642-9

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