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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2018-06, Vol.96 (6), p.575-583
• Main Authors: Eguchi, Akiko, Koyama, Yukinori, Wree, Alexander, Johnson, Casey D., Nakamura, Ryota, Povero, Davide, Kneiber, David, Tameda, Masahiko, Contreras, Patricia, Spada, Al, Feldstein, Ariel E.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Bile; Bile Ducts - surgery; Biomedical and Life Sciences; Biomedicine; Caspase inhibitors; Caspase Inhibitors - therapeutic use; Cell activation; Cell death; Cirrhosis; Disease Models, Animal; Endothelial cells; Fibrosis; Flow cytometry; Hepatocytes; Human Genetics; Hypertension; Hypertension, Portal - drug therapy; Internal Medicine; Ligation; Liver; Liver cirrhosis; Mice; Mice, Inbred C57BL; Microparticles; Molecular Medicine; Original Article; Patients; Pentanoic Acids - therapeutic use; Rodents; Short term
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-018-1642-9

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