Original Articles
Effects of geranyl-geranyl-acetone administration before heat shock preconditioning for conferring tolerance against ischemia-reperfusion injury in rat livers,☆☆

https://doi.org/10.1067/mlc.2000.106806Get rights and content

Abstract

The effect of geranyl-geranyl-acetone (GGA) administration before heat shock preconditioning on heat shock protein (HSP) 72 induction and on the acquisition of tolerance against ischemia-reperfusion injury was studied in rat livers. Male Wistar rats were divided into four groups: a control group (group C); a GGA group (group G); a simple heat shock group (group VH); and a heat shock with GGA premedication group (group GH). Five-, 10-, and 15-minute periods of heat shock preconditioning at 42°C were performed in groups VH and GH. Subgroups were determined according to the period of heat shock exposure. After a 48-hour recovery, rats in groups C, VH5, VH15, and GH5 received a 30-minute period of hepatic ischemia. Induction of HSP72, survival rates, and changes in biochemical and histologic parameters were compared among the groups. Five-minute heat shock preconditioning was not enough to induce HSP72. However, livers in group GH5 expressed approximately the same amount of HSP72 as those in group VH15. The expression of HSP72 in group GH15 was stronger than that found in group VH15. The degree and location of HSP72 expression were not different between groups GH5 and VH15. Seven-day survival was significantly better in groups GH5 (16/16) and VH15 (15/16) than in group C (8/16) or VH5 (9/16). The recovery of adenosine triphosphate in liver tissue was faster, and the release of liver-related enzymes during reperfusion was lower in groups GH5 and VH15 than in group C or VH5. Administration of GGA before heat shock preconditioning augmented the induction of HSP72 by decreasing the threshold for triggering the stress response. (J Lab Clin Med 2000;135:465-75)

Section snippets

Animals

This study was conducted in accordance with the Animal Protection Guidelines of Kyoto University. Two hundred male Wistar rats (Shizuoka Laboratory Animal Center, Hamamatsu, Japan) weighing between 230 and 260 g (10-11 weeks of age) were used. They were housed in chip-bedded cages in an air-conditioned room (24°C ± 1°C) with controlled 12-hour light/dark cycles. Rats were permitted free access to water and standard rat chow.

Administration of GGA

After overnight fasting, each rat in the GGA groups was given 8 mL/kg

Detection of HSP72

Fig 2, A , shows the production of HSP72 in liver tissue 48 hours after heat shock exposure in liver tissue in all groups.

. A, Production of HSP72 48 hours after heat shock exposure in liver tissue. Protein concentrations are 3 μg per lane in samples and 0.005 μg per lane in the positive control (HSP72). B, Densitometrical quantification of HSP72 from 4 rats. To standardize blotting condition on each film, 0.005 μg of HSP72 (SPP755) was simultaneously electrophoresed on the gels as an external

Discussion

There are two ways to reduce the heat shock stress necessary to induce HSP72: one is to shorten the duration of exposure, and the other is to decrease the temperature. The present study demonstrated that the administration of GGA before heat shock increases the responsiveness of hepatocytes to heat shock stress. Neither an administration of GGA alone nor a 5-minute heat shock at 42°C was enough to trigger a stress response or to induce detectable levels of HSP72 in hepatocytes. After

Acknowledgements

We thank Eisai Co, Ltd, for the generous gift of GGA and Dr Koji Uchida (Laboratory of Food and Biodynamics, Nagoya University School of Agriculture, Nagoya, Japan) for providing polyclonal antibody against HNE-modified proteins.

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    Supported in part by grants from the Scientific Research Fund of the Ministry of Education, Japan (grants 09307026 and 10557120) and in part by The Japan Society for the Promotion of Science, Japan (grant JSPS-RFTF 96I00204).

    ☆☆

    Reprint requests: Yuzo Yamamoto, MD, Department of Gastroenterological Surgery, Kyoto University, Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

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