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Transplantation. 2008 Feb 15;85(3):323-30. doi: 10.1097/TP.0b013e31816168f9.

Inducible nitric oxide synthase-nitric oxide plays an important role in acute and severe hypoxic injury to pancreatic beta cells.

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  • 1Division of Endocrinology & Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.

Abstract

BACKGROUND:

Islet transplantation is a potential strategy to cure type 1 diabetes mellitus. However, a substantial part of the islet graft becomes nonfunctional due to several factors including hypoxia. However, the precise mechanism of cell damage is largely unknown in hypoxic exposure to pancreatic beta cells. The aim of the present study was to investigate whether acute and severe hypoxic injury could involve inducible nitric oxide synthase (iNOS)-nitric oxide (NO) signaling in beta cells.

METHODS:

The rat beta cell line (INS-1) and primary rat islets were incubated in an anoxic chamber. Cell viability was determined by propium iodide staining or cell counting kit. The expression of iNOS mRNA and protein was examined using reverse-transcription polymerase chain reaction and Western blot analysis. NO production was measured as nitrite accumulation by Griess reagent method.

RESULTS:

After hypoxic exposure, marked cell death occurred in INS-1 cells and rat islets, accompanied by increase in activated caspase-3 expression. NO production was increased in the culture medium in a time-dependent manner. Increase in expression of iNOS mRNA and protein was found. Pretreatment with a selective iNOS inhibitor, 1400W, significantly prevented cell death during hypoxia. In addition, hypoxia activated c-Jun N-terminal kinase (JNK) significantly, but the addition of 1400W inhibited hypoxia-induced JNK phosphorylation.

CONCLUSIONS:

Our data suggest that iNOS-NO plays an important role in acute and severe hypoxic injury to pancreatic beta cells. Therefore, iNOS-NO might be a potential therapeutic target for preserving beta cell survival in islet transplantation through prevention of hypoxia-mediated cell death.

PMID:
18301327
[PubMed - indexed for MEDLINE]
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