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

Research output: Contribution to journalArticle

44 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 2008
Externally publishedYes

Fingerprint

Warm Ischemia
Arginase
Reperfusion
Arginine
Liver
Ischemia
Nitric Oxide
Nitric Oxide Synthase
Reperfusion Injury
Serum
Amino Acids
Citrulline
Nitric Oxide Synthase Type II
Inbred C57BL Mouse
Interleukin-6
Animals
Hepatocytes
Tissue
High Pressure Liquid Chromatography
Messenger RNA

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion. / Jeyabalan, Geetha; Klune, John R.; Nakao, Atsunori; Martik, Nicole; Wu, Guoyao; Tsung, Allan; Geller, David A.

In: Nitric Oxide - Biology and Chemistry, Vol. 19, No. 1, 08.2008, p. 29-35.

Research output: Contribution to journalArticle

Jeyabalan, Geetha ; Klune, John R. ; Nakao, Atsunori ; Martik, Nicole ; Wu, Guoyao ; Tsung, Allan ; Geller, David A. / Arginase blockade protects against hepatic damage in warm ischemia-reperfusion. In: Nitric Oxide - Biology and Chemistry. 2008 ; Vol. 19, No. 1. pp. 29-35.
@article{edaf29618fdb489cb1e55491d65de2f2,
title = "Arginase blockade protects against hepatic damage in warm ischemia-reperfusion",
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.",
keywords = "Arginase, Arginine, Inflammation, Ischemia reperfusion, Liver, Nitric oxide",
author = "Geetha Jeyabalan and Klune, {John R.} and Atsunori Nakao and Nicole Martik and Guoyao Wu and Allan Tsung and Geller, {David A.}",
year = "2008",
month = "8",
doi = "10.1016/j.niox.2008.04.002",
language = "English",
volume = "19",
pages = "29--35",
journal = "Nitric Oxide - Biology and Chemistry",
issn = "1089-8603",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

AU - Jeyabalan, Geetha

AU - Klune, John R.

AU - Nakao, Atsunori

AU - Martik, Nicole

AU - Wu, Guoyao

AU - Tsung, Allan

AU - Geller, David A.

PY - 2008/8

Y1 - 2008/8

N2 - 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.

AB - 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.

KW - Arginase

KW - Arginine

KW - Inflammation

KW - Ischemia reperfusion

KW - Liver

KW - Nitric oxide

UR - http://www.scopus.com/inward/record.url?scp=45949105789&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45949105789&partnerID=8YFLogxK

U2 - 10.1016/j.niox.2008.04.002

DO - 10.1016/j.niox.2008.04.002

M3 - Article

VL - 19

SP - 29

EP - 35

JO - Nitric Oxide - Biology and Chemistry

JF - Nitric Oxide - Biology and Chemistry

SN - 1089-8603

IS - 1

ER -