Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension in a murine model of common bile-duct ligation
- 330 Downloads
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.
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
KeywordsPortal hypertension Cirrhosis Pan-caspase inhibitor Extracellular vesicles
UCSD Neuroscience Core for microscopy is supported by a grant NS047101.
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.
- 4.Eguchi A, Lazaro RG, Wang J, Kim J, Povero D, Willliams B, Ho SB, Starkel P, Schnabl B, Ohno-Machado L et al (2017) Extracellular vesicles released by hepatocytes from gastric infusion model of alcoholic liver disease contain a MicroRNA barcode that can be detected in blood. Hepatology 65:475–490PubMedCrossRefGoogle Scholar
- 5.Verma VK, Li H, Wang R, Hirsova P, Mushref M, Liu Y, Cao S, Contreras PC, Malhi H, Kamath PS, Gores GJ, Shah VH (2016) Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol 64:651–660PubMedCrossRefGoogle Scholar
- 8.Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, Carreras MC, Poderoso JJ, Gores GJ (2015) The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int : Off J Int Assoc Study Liver 35:953–966CrossRefGoogle Scholar
- 9.Witek RP, Stone WC, Karaca FG, Syn WK, Pereira TA, Agboola KM, Omenetti A, Jung Y, Teaberry V, Choi SS, Guy CD, Pollard J, Charlton P, Diehl AM (2009) Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology 50:1421–1430PubMedCrossRefGoogle Scholar
- 12.Baskin-Bey ES, Washburn K, Feng S, Oltersdorf T, Shapiro D, Huyghe M, Burgart L, Garrity-Park M, van Vilsteren FG, Oliver LK et al (2007) Clinical trial of the pan-caspase inhibitor, IDN-6556, in human liver preservation injury. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 7:218–225CrossRefGoogle Scholar
- 13.Eguchi A, De Mollerat Du Jeu X, Johnson CD, Nektaria A, Feldstein AE (2016) Liver bid suppression for treatment of fibrosis associated with non-alcoholic steatohepatitis. J Hepatol 64: 699–707. DOI Google Scholar
- 18.Povero D, Eguchi A, Li H, Johnson CD, Papouchado BG, Wree A, Messer K, Feldstein AE (2014) Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One 9:e113651. https://doi.org/10.1371/journal.pone.0113651 PubMedPubMedCentralCrossRefGoogle Scholar
- 19.Povero D, Eguchi A, Niesman IR, Andronikou N, de Mollerat du Jeu X, Mulya A, Berk M, Lazic M, Thapaliya S, Parola M, et al. (2013) Lipid-induced toxicity stimulates hepatocytes to release angiogenic microparticles that require Vanin-1 for uptake by endothelial cells. Sci Signal 6: ra88. DOI Google Scholar
- 21.Garcia-Tsao G, Fuchs M, Shiffman ML, Chan JL, Morris M, Yamashita M, Spada AP, Hagerty D, Bosch J Emricasan (IDN-6556) administered orally for 28 days lowers portal pressure in patients with compensated cirrhosis and severe portal hypertension. Hepatology 62: 1382AGoogle Scholar