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Overexpression of spermidine/spermine N 1-acetyltransferase or treatment with N 1-N 11-diethylnorspermine attenuates the severity of zinc-induced pancreatitis in mouse

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Abstract

Depletion of pancreatic intracellular polyamine pools has been observed in acute pancreatitis both in the animal models and in humans. In this study, the wild-type mice, polyamine catabolic enzyme spermidine/spermine N 1-acetyltransferase overexpressing (SSAT mice) and SSAT-deficient mice were used to characterize the new zinc-induced acute pancreatitis mouse model and study the role of polyamines and polyamine catabolism in this model. Intraperitoneal zinc injection induced acute necrotizing pancreatitis in wild-type mice as well as in SSAT-overexpressing and SSAT-deficient mice. Serum α-amylase activity was significantly increased in all zinc-treated mice compared with the untreated controls. However, the α-amylase activities in SSAT mice were constantly lower than those in the other groups. Histopathological examination of pancreatic tissue revealed edema, acinar cell necrosis and necrotizing inflammation, typical for acute pancreatitis. Compared with the other zinc-treated mice less damage according to the histopathological analysis was observed in the pancreatic tissue of SSAT mice. Levels of intracellular spermidine, and occasionally spermine, were significantly decreased in pancreases of all zinc-treated animals and SSAT enzyme activity was enhanced both in wild-type and SSAT mice. Interestingly, a spermine analog, N 1, N 11-diethylnorspermine (DENSpm), enhanced the proliferation of pancreatic cells and reduced the severity of zinc-induced pancreatitis in wild-type mice. The results show that in mice a single intraperitoneal zinc injection causes acute necrotizing pancreatitis accompanied by decrease of intracellular polyamine pools. The study supports the important role of polyamines for the integrity and function of the pancreas. In addition, the study suggests that whole body overexpression of SSAT obtained in SSAT mice reduces inflammatory pancreatic cell injury.

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Abbreviations

SSAT:

Spermidine/spermine N 1-acetyltranferase

DENSpm:

N 1, N 11-Bis(ethyl)norspermine

ODC:

Ornithine decarboxylase

SAMDC:

S-Adenosylmethionine decarboxylase

MT:

Metallothionein

BSA:

Bovine serum albumin

PCNA:

Proliferating cell nuclear antigen

HRP:

Horseradish peroxidase

DBA:

Diaminobenzidine

ALAT:

l-Alanine aminotrasferase

NF-κB:

Nuclear factor-κB

TNF-α:

Tumor necrosis factor-alpha

ROS:

Reactive oxygen species

HIF-1α:

Hypoxia-inducible factor-1α

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Acknowledgments

We gratefully acknowledge Ms Tuula Reponen, Ms Sisko Juutinen, Ms Anne Karppinen, Ms Arja Korhonen and Ms Marita Heikkinen for their skilful technical assistance. This work was supported by the Academy of Finland.

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Authors and Affiliations

  1. Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland

    Anne Uimari, Mari Merentie, Sini Pirnes-Karhu & Leena Alhonen

  2. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland and Unit of Pathology, Kuopio University Hospital, P.O. Box 1627, FI-70211, Kuopio, Finland

    Reijo Sironen

  3. Department of Biosciences, Laboratory of Chemistry, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland

    Sirpa Peräniemi

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  1. Anne Uimari
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Correspondence to Anne Uimari.

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Uimari, A., Merentie, M., Sironen, R. et al. Overexpression of spermidine/spermine N 1-acetyltransferase or treatment with N 1-N 11-diethylnorspermine attenuates the severity of zinc-induced pancreatitis in mouse. Amino Acids 42, 461–471 (2012). https://doi.org/10.1007/s00726-011-1025-9

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