Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis

hideo uehara, Tomohiko Akahoshi, Hirohumi Kawanaka, Naotaka Hashimoto, Yoshihiro Nagao, Morimasa Tomikawa, Akinobu Taketomi, Ken Shirabe, Makoto Hashizume, Yoshihiko Maehara

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Aim: Splenectomy or partial splenic embolism has been reported to improve liver function in patients with hypersplenism and liver dysfunction. The aim of this study was to investigate the mechanism of improvement after splenectomy. Methods: Liver cirrhosis was induced by bile duct ligation (BDL). Rats underwent sham operation, splenectomy (Sp group), BDL, or BDL plus splenectomy (BDL+Sp group), and were subjected to experiments at 2weeks after the operation. Portal venous pressure (PVP) and hepatic tissue blood flow (HTBF) were measured in each group. The plasma concentration of endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS), RhoA and Rho-kinase expressions were studied. Results: There were significant differences in PVP (17.9±0.91 vs 23.3±3.91cmH 2O; P<0.01) and HTBF (16.6±1.72 vs 13.3±1.82mL/min; P<0.01) between the BDL+Sp and BDL groups. In the liver of BDL rats, eNOS phosphorylation and NOx levels were decreased, accompanied by RhoA activation compared with the BDL+Sp group. Splenectomy decreased serum ET-1 levels, RhoA activation and consequently increased eNOS phosphorylation. Conclusion: ET-1 derived from the spleen might increase intrahepatic resistance by downregulating Rho signaling in liver cirrhosis. Splenectomy for splenomegaly in liver cirrhosis might partially improve liver function by enhancing intrahepatic microcirculation.

Original languageEnglish
Pages (from-to)1039-1047
Number of pages9
JournalHepatology Research
Volume42
Issue number10
DOIs
Publication statusPublished - Oct 1 2012

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rho-Associated Kinases
Biliary Liver Cirrhosis
Endothelin-1
Bile Ducts
Ligation
Splenectomy
Spleen
Liver Cirrhosis
Liver
Portal Pressure
Nitric Oxide Synthase Type III
Phosphorylation
Hypersplenism
Splenomegaly
Microcirculation
Embolism
Liver Diseases
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Infectious Diseases

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Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis. / uehara, hideo; Akahoshi, Tomohiko; Kawanaka, Hirohumi; Hashimoto, Naotaka; Nagao, Yoshihiro; Tomikawa, Morimasa; Taketomi, Akinobu; Shirabe, Ken; Hashizume, Makoto; Maehara, Yoshihiko.

In: Hepatology Research, Vol. 42, No. 10, 01.10.2012, p. 1039-1047.

Research output: Contribution to journalArticle

uehara, H, Akahoshi, T, Kawanaka, H, Hashimoto, N, Nagao, Y, Tomikawa, M, Taketomi, A, Shirabe, K, Hashizume, M & Maehara, Y 2012, 'Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis', Hepatology Research, vol. 42, no. 10, pp. 1039-1047. https://doi.org/10.1111/j.1872-034X.2012.01021.x
uehara, hideo ; Akahoshi, Tomohiko ; Kawanaka, Hirohumi ; Hashimoto, Naotaka ; Nagao, Yoshihiro ; Tomikawa, Morimasa ; Taketomi, Akinobu ; Shirabe, Ken ; Hashizume, Makoto ; Maehara, Yoshihiko. / Endothelin-1 derived from spleen-activated Rho-kinase pathway in rats with secondary biliary cirrhosis. In: Hepatology Research. 2012 ; Vol. 42, No. 10. pp. 1039-1047.
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AU - uehara, hideo

AU - Akahoshi, Tomohiko

AU - Kawanaka, Hirohumi

AU - Hashimoto, Naotaka

AU - Nagao, Yoshihiro

AU - Tomikawa, Morimasa

AU - Taketomi, Akinobu

AU - Shirabe, Ken

AU - Hashizume, Makoto

AU - Maehara, Yoshihiko

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N2 - Aim: Splenectomy or partial splenic embolism has been reported to improve liver function in patients with hypersplenism and liver dysfunction. The aim of this study was to investigate the mechanism of improvement after splenectomy. Methods: Liver cirrhosis was induced by bile duct ligation (BDL). Rats underwent sham operation, splenectomy (Sp group), BDL, or BDL plus splenectomy (BDL+Sp group), and were subjected to experiments at 2weeks after the operation. Portal venous pressure (PVP) and hepatic tissue blood flow (HTBF) were measured in each group. The plasma concentration of endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS), RhoA and Rho-kinase expressions were studied. Results: There were significant differences in PVP (17.9±0.91 vs 23.3±3.91cmH 2O; P<0.01) and HTBF (16.6±1.72 vs 13.3±1.82mL/min; P<0.01) between the BDL+Sp and BDL groups. In the liver of BDL rats, eNOS phosphorylation and NOx levels were decreased, accompanied by RhoA activation compared with the BDL+Sp group. Splenectomy decreased serum ET-1 levels, RhoA activation and consequently increased eNOS phosphorylation. Conclusion: ET-1 derived from the spleen might increase intrahepatic resistance by downregulating Rho signaling in liver cirrhosis. Splenectomy for splenomegaly in liver cirrhosis might partially improve liver function by enhancing intrahepatic microcirculation.

AB - Aim: Splenectomy or partial splenic embolism has been reported to improve liver function in patients with hypersplenism and liver dysfunction. The aim of this study was to investigate the mechanism of improvement after splenectomy. Methods: Liver cirrhosis was induced by bile duct ligation (BDL). Rats underwent sham operation, splenectomy (Sp group), BDL, or BDL plus splenectomy (BDL+Sp group), and were subjected to experiments at 2weeks after the operation. Portal venous pressure (PVP) and hepatic tissue blood flow (HTBF) were measured in each group. The plasma concentration of endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS), RhoA and Rho-kinase expressions were studied. Results: There were significant differences in PVP (17.9±0.91 vs 23.3±3.91cmH 2O; P<0.01) and HTBF (16.6±1.72 vs 13.3±1.82mL/min; P<0.01) between the BDL+Sp and BDL groups. In the liver of BDL rats, eNOS phosphorylation and NOx levels were decreased, accompanied by RhoA activation compared with the BDL+Sp group. Splenectomy decreased serum ET-1 levels, RhoA activation and consequently increased eNOS phosphorylation. Conclusion: ET-1 derived from the spleen might increase intrahepatic resistance by downregulating Rho signaling in liver cirrhosis. Splenectomy for splenomegaly in liver cirrhosis might partially improve liver function by enhancing intrahepatic microcirculation.

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