Signal pathway responsible for hepatocyte preconditioning by nitric oxide.

Abstract

Nitric oxide (NO) improves liver resistance to hypoxia/reperfusion injury acting as a mediator of hepatic preconditioning. However, the mechanisms involved are still poorly understood. In this study, we have investigated the mechanisms by which short-term exposure to the NO donor (Z)-1-(N-methyl-N-[6-(N-methylammoniohexyl)amino])-diazen-1-ium-1,2-diolate (NOC-9) increases hepatocyte tolerance to hypoxic injury. Isolated rat hepatocytes preincubated 15 min with NOC-9 (0.250 mM) became resistant to the killing caused by hypoxia. NOC-9 cytoprotection did not involve the activation of protein kinase C, but was instead blocked by inhibiting soluble guanylate cyclase with 1H-(1,2,4)-oxadiazolo-(4,3) quinoxalin-1-one (ODQ) (50 microM) or cGMP-dependent kinase (cGK) with KT 5823 (5 microM). Conversely, cGMP analogue, 8Br-cGMP (50 microM) mimicked the effect of NOC-9. Western blot analysis revealed that hepatocyte treatment with NOC-9 or 8Br-cGMP significantly increased dual phosphorylation of p38 MAPK. The activation of p38 MAPK was abolished by inhibiting guanylate cyclase or cGK. Pretreatment with NO significantly reduced intracellular Na(+) accumulation in hypoxic hepatocytes. This effect was reverted by KT 5823 as well as by the p38 MAPK inhibitor SB203580. SB203580 also reverted NOC-9 protection against hypoxic injury. Altogether, these results demonstrated that NO can induce hepatic preconditioning by activating p38 MAPK through a guanylate cyclase/cGK-mediated pathway.

• Authors: Rita Carini, Maria Grazia De Cesaris, Roberta Splendore, Cinzia Domenicotti, Maria Paola Nitti, Maria Adelaide Pronzato, Emanuele Albano
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 34 Issue 8 Pg. 1047-55 (Apr 15 2003) ISSN: 0891-5849 [Print] United States
• PMID: 12684089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbazoles
• Enzyme Inhibitors
• Free Radicals
• Imidazoles
• Indoles
• Pyridines
• KT 5823
• Nitric Oxide
• Sodium
• Cyclic GMP-Dependent Protein Kinases
• Protein Kinase C
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Guanylate Cyclase
• SB 203580

Topics

• Animals
• Blotting, Western
• Carbazoles (pharmacology)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Free Radicals
• Guanylate Cyclase (metabolism)
• Hepatocytes (metabolism)
• Hypoxia
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Ischemic Preconditioning
• Liver (injuries, pathology)
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• Nitric Oxide (metabolism)
• Phosphorylation
• Protein Kinase C (metabolism)
• Pyridines (pharmacology)
• Rats
• Signal Transduction
• Sodium (metabolism)
• Time Factors
• p38 Mitogen-Activated Protein Kinases