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Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3

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Abstract

Purpose

Pharmacological preconditioning, including that with geranylgeranylacetone (GGA) and volatile anesthetics, has been shown to confer cardiac protection from ischemia/reperfusion injury although the mechanisms for this protection are poorly understood. Caveolins, integral membrane proteins that act as scaffolding proteins in caveolar membranes, localize molecules involved in cardiac protection. We have tested the hypothesis that caveolin-3 (Cav-3), the predominant isoform in cardiac myocytes, is essential for the synergistic effect observed between GGA and volatile anesthetics.

Methods

Mice were randomly assigned to receive GGA, isoflurane [0.5 and 1.0 minimum alveolar concentration (MAC)], or GGA + isoflurane (0.5 MAC). An in vivo mouse model of ischemia/reperfusion injury was tested in wild-type and Cav-3 knockout mice, and the infarct size was determined. Biochemical assays were also performed in excised hearts.

Results

Geranylgeranylacetone and therapeutic isoflurane (1.0 MAC) independently reduced infarct size (31.6 ± 6.1 and 28.0 ± 5.0 % of the area at risk, respectively; n = 10) as compared to the controls (45.8 ± 9.4 %; n = 10). The combination GGA + sub-therapeutic isoflurane (0.5 MAC) further decreased the infarct size to 19.3 ± 5.1 % (n = 10). Preconditioning [GGA, isoflurane (1.0 MAC), and GGA + isoflurane] increased the amount of Cav-3 protein in the discontinuous sucrose-gradient buoyant fractions. Additionally, cardiac protection was not observed in Cav-3 knockout mice following the administration of GGA, isoflurane, and GGA + isoflurane.

Conclusions

Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.

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Acknowledgments

The research was supported by JSPS KAKENHI Numbers 23592994, 24592300, 25462404, and 25462405 from Japan Society for the Promotion of Science, Tokyo.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Tokushima, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan

    Yasuo M. Tsutsumi, Yousuke T. Horikawa, Yoko Sakai, Eisuke Hamaguchi, Asuka Kasai, Noriko Kambe & Katsuya Tanaka

  2. Department of Nutrition, University of Tokushima, Tokushima, Japan

    Rie Tsutsumi

  3. Department of Dental Anesthesiology, University of Tokushima, Tokushima, Japan

    Hiroshi Kitahata

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  1. Yasuo M. Tsutsumi
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Correspondence to Yasuo M. Tsutsumi.

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Tsutsumi, Y.M., Tsutsumi, R., Horikawa, Y.T. et al. Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3. J Anesth 28, 733–739 (2014). https://doi.org/10.1007/s00540-014-1816-8

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  • DOI: https://doi.org/10.1007/s00540-014-1816-8

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