Transgenic Rats as Models for Studying the Role of Ornithine Decarboxylase Expression in Permanent Middle Cerebral Artery Occlusion

Lukkarinen, Jouko A.; Gröhn, Olli; Sinervirta, Riitta; Järvinen, Aki; Kauppinen, Risto A.; Jänne, Juhani; Alhonen, Leena

doi:10.1161/01.str.28.3.639

Cited by 27 publications

(38 citation statements)

References 36 publications

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“…Among them, transgenic rats and mice overexpressing human ODC have been produced and used by the Alhonen group to study the role of ODC expression on the development of induced brain infarct. These transgenic rats had a 7-fold higher accumulation of putrescine in the brain in comparison to syngenic rats, but the levels of the higher polyamines spermidine and spermine remained constant and there were no significant effects on the development of the ischemic stroke lesion, showing that a several-fold increase in putrescine alone has no impact on this process [23].…”

Section: Polyamine Synthesis and Functionsmentioning

confidence: 90%

The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis

Forte¹,

Hellstrand²,

Nilsson³

et al. 2011

CVP

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Section: Polyamine Synthesis and Functionsmentioning

confidence: 90%

The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis

Forte¹,

Hellstrand²,

Nilsson³

et al. 2011

CVP

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“…Generation of Transgenic Rats-The production of transgenic Wistar rats harboring the metallothionein-SSAT fusion gene (10) has been described earlier (8,11). Partial hepatectomy was carried out according to the original method of Higgins and Anderson (12).…”

Section: Methodsmentioning

confidence: 99%

A Polyamine Analogue Prevents Acute Pancreatitis and Restores Early Liver Regeneration in Transgenic Rats with Activated Polyamine Catabolism

Räsänen

Alhonen

Sinervirta

et al. 2002

Journal of Biological Chemistry

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We recently generated a transgenic rat model for acute pancreatitis, which was apparently caused by a massive depletion of pancreatic polyamines spermidine and spermine due to inducible activation of their catabolism (Alhonen, L., Parkkinen, J. J., Keinä nen, T., Sinervirta, R., Herzig, K. H., and Jä nne, J. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 8290 -8295). When subjected to partial hepatectomy, these animals showed striking activation of polyamine catabolism at 24 h postoperatively with a profound decrease in hepatic spermidine and spermine pools and failure to initiate liver regeneration. Here we show that pancreatitis in this model could be totally prevented, as judged by histopathology and plasma ␣-amylase activity, by administration of 1-methylspermidine, a metabolically stable analogue of spermidine. Similarly, the analogue, given prior to partial hepatectomy, restored early liver regeneration in the transgenic rats, as indicated by a dramatic increase in the number of proliferating cell nuclear antigen-positive hepatocytes from about 1% to more than 40% in response to the drug. The present results suggest that the extremely high concentration of spermidine in the pancreas, in fact the highest in the mammalian body, may have a critical role in maintaining organ integrity. The failure to initiate liver regeneration in the absence of sufficient hepatic polyamine pools similarly indicates that polyamines are required for proper commencement of the regenerative process.The polyamines spermidine and spermine and their precursor putrescine are intimately associated with growth and differentiation of mammalian cells, yet their exact cellular functions have not been solved (1). In attempts to elucidate the physiological roles of the polyamines, we have generated a number of transgenic mouse and rat lines with genetically altered polyamine metabolism. The activation of polyamine biosynthesis through an overexpression of ornithine decarboxylase brings about many interesting phenotypic changes, such as male infertility (2, 3), yet these studies are complicated by the fact that overexpression of ornithine decarboxylase only expands tissue putrescine pools as the latter diamine is not further converted to spermidine and spermine (4, 5). Much more severe distortion of tissue polyamine pools has been achieved by activation of polyamine catabolism through an overexpression of spermidine/spermine N 1 -acetyltransferase (SSAT) 1 in transgenic rodents. The latter enzyme catalyzes the rate-controlling reaction in the catabolism of spermidine and spermine. After being acetylated, spermidine is converted to putrescine and spermine to spermidine by the action of polyamine oxidase (6). Overexpression of SSAT in transgenic rodents results in profound changes in tissue polyamine pools, such as the massive accumulation of putrescine, appearance of N 1 -acetylspermidine, and decreases in spermidine and/or spermine pools (7). The alterations in polyamine homeostasis are accompanied by bizarre phenotypic changes, such as the earl...

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“…The production of transgenic Wistar rats has been described (11). Briefly, the donor females were superovulated and mated with mature males, and the zygotes were collected and microinjected with the metallothionein-SSAT gene.…”

Section: Methodsmentioning

confidence: 99%

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Alhonen

Parkkinen²,

Keinänen³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine͞spermine N 1 -acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N 1 -acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N 1 ,N 2 -bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N 1 ,N 11 -diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N 1 ,N 11 -diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.I ntracellular polyamine levels are tightly maintained by a number of mechanisms, suggesting their importance for cell function. This polyamine homeostasis is controlled by their biosynthesis, interconversion, catabolism, secretion, and uptake. Polyamine biosynthesis is regulated by the activities of ornithine and S-adenosylmethionine decarboxylases. Overexpression of ornithine decarboxylase in transgenic rodents affected spermatogenesis (1, 2), rendered animals more resistant to chemically or electrically induced seizure activity (3) and to ischemic insults (4), and enhanced skin papilloma formation (5). However, the activation of polyamine biosynthesis caused by overexpression of ornithine decarboxylase did not result in enhanced accumulation of the higher polyamines spermidine and spermine. Polyamine catabolism is controlled by the activity of spermidine͞spermine N 1 -acetyltransferase (SSAT; refs. 6 and 7). The acetylated products are oxidized further by the polyamine oxidase (PAO) to spermidine and putrescine. We recently generated transgenic mouse lines with ...

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Transgenic Rats as Models for Studying the Role of Ornithine Decarboxylase Expression in Permanent Middle Cerebral Artery Occlusion

Cited by 27 publications

References 36 publications

The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis

The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis

A Polyamine Analogue Prevents Acute Pancreatitis and Restores Early Liver Regeneration in Transgenic Rats with Activated Polyamine Catabolism

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

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