Rho-kinase as a novel gene therapeutic target in treatment of cold ischemia/reperfusion-induced acute lethal liver injury: Effect on hepatocellular NADPH oxidase system

S. Shiotani, M. Shimada, A. Taketomi, Yuji Soejima, Tomoharu Yoshizumi, K. Hashimoto, H. Shimokawa, Yoshihiko Maehara

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In the transplant surgery, reactive oxygen species (ROS) from the reperfused tissue cause ischemia-reperfusion injury, resulting in the primary graft failure. We have recently reported that Rho-kinase, an effecter of the small GTPase Rho, plays an important role in the ROS production in the hyperacute phase of reperfusion; however, the sources and mechanisms of the ROS production remain to be elucidated. The aim of this study was to investigate the source of ROS production with a special reference to Rho-kinase to develop a new strategy against ischemia-reperfusion injury. In an in vivo rat model of liver transplantation, Kupffer cells in the graft were depleted using liposome-encapsulated dichloromethylene diphosphonate to examine the source of ROS production. The effect of adenoviral-mediated overexpression of a dominant-negative Rho-kinase (AdDNRhoK) in hepatocytes in the graft was also examined. Kupffer cells were not involved in the ROS production, whereas the AdDNRhoK transfection to hepatocytes significantly suppressed the ROS production. Furthermore, the ROS production was dose-dependently inhibited by apocynin, an NADPH oxidase inhibitor. Expression of DNRhoK also suppressed the release of pro-inflammatory cytokines, and ameliorated the lethal liver injury with a significant prolongation of the survival. These results suggest that the Rho-kinase-mediated pathway plays a crucial role in the ROS production through NADPH oxidase in hepatocytes during the hyperacute phase of reperfusion in vivo. Thus, Rho-kinase in hepatocytes may be a new therapeutic target for the prevention of primary graft failure in liver transplantation.

Original languageEnglish
Pages (from-to)1425-1433
Number of pages9
JournalGene Therapy
Volume14
Issue number19
DOIs
Publication statusPublished - Oct 1 2007

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Cold Ischemia
rho-Associated Kinases
NADPH Oxidase
Reperfusion
Reactive Oxygen Species
Liver
Wounds and Injuries
Genes
Hepatocytes
Transplants
Kupffer Cells
Therapeutics
Reperfusion Injury
Liver Transplantation
Monomeric GTP-Binding Proteins
Primary Prevention
Transfection
Cytokines

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Rho-kinase as a novel gene therapeutic target in treatment of cold ischemia/reperfusion-induced acute lethal liver injury : Effect on hepatocellular NADPH oxidase system. / Shiotani, S.; Shimada, M.; Taketomi, A.; Soejima, Yuji; Yoshizumi, Tomoharu; Hashimoto, K.; Shimokawa, H.; Maehara, Yoshihiko.

In: Gene Therapy, Vol. 14, No. 19, 01.10.2007, p. 1425-1433.

Research output: Contribution to journalArticle

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