Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

Geetha Jeyabalan, John R. Klune, Atsunori Nakao, Nicole Martik, Guoyao Wu, Allan Tsung, David A. Geller

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45 Citations (Scopus)

Abstract

Background: Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R. Methods: C57BL/6 mice underwent partial liver warm I/R and were treated intraperitoneally with either nor-NOHA (100 mg/kg) or saline. Serum and tissue samples were collected to measure liver enzyme levels, amino acids, and inflammatory mediators. The agent nor-NOHA (100 mg/kg) was administered 15 min before ischemia and immediately after reperfusion. Serum amino acid analysis was performed using HPLC. Results: Arginase activity after hepatic I/R peaked at 3-6 h after reperfusion and resulted in a 10-fold drop in circulating arginine levels. Treatment with nor-NOHA inhibited arginase activity and reversed the arginine depletion after I/R while simultaneously increasing serum nitric oxide. In addition, circulating citrulline, a product of NOS activity, was increased in nor-NOHA-treated animals compared to controls. Inhibition of arginase also resulted in protection from hepatic I/R-induced damage in association with markedly lower hepatic TNF, IL-6, and inducible NOS mRNA levels compared to controls. Conclusion: Arginase blockade represents a potentially novel strategy to combat liver injury under conditions of arginine deficiency. This protection may be mediated through the arginine-NO pathway.

Original languageEnglish
Pages (from-to)29-35
Number of pages7
JournalNitric Oxide - Biology and Chemistry
Volume19
Issue number1
DOIs
Publication statusPublished - Aug 1 2008

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Keywords

  • Arginase
  • Arginine
  • Inflammation
  • Ischemia reperfusion
  • Liver
  • Nitric oxide

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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