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Journal of Cellular Biochemistry

Cyclooxygenase-2 over-expression inhibits liver apoptosis induced by hyperglycemia

Authors

  • Daniel E.A. Francés,

    1. Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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  • Paola I. Ingaramo,

    1. Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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  • Rafael Mayoral,

    1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, IIBM, Consejo Superior de Investigaciones Científicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Villaroel 170, 08036 Barcelona, Spain
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  • Paqui Través,

    1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, IIBM, Consejo Superior de Investigaciones Científicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
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  • Marta Casado,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Villaroel 170, 08036 Barcelona, Spain
    2. Instituto de Biomedicina de Valencia, IBV, CSIC, Jaume Roig 11, 46010 Valencia, Spain
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  • Ángela M. Valverde,

    1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, IIBM, Consejo Superior de Investigaciones Científicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Ciberdem), Paseo de la Bosanova 69, 08017 Barcelona, Spain
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  • Paloma Martín-Sanz PhD,

    Corresponding author
    1. Instituto de Investigaciones Biomédicas ‘Alberto Sols’, IIBM, Consejo Superior de Investigaciones Científicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Villaroel 170, 08036 Barcelona, Spain
    • Instituto de Investigaciones Biomédicas ‘Alberto Sols’, IIBM, Consejo Superior de Investigaciones Científicas, CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Villaroel 170, 08036 Barcelona, Spain.
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  • Cristina E. Carnovale PhD

    Corresponding author
    1. Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
    • Institute of Experimental Physiology (CONICET), Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario, Suipacha 570, 2000-Rosario, Argentina.
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  • Daniel E.A. Francés and Paola I. Ingaramo contributed equally to this work.

Abstract

Increased expression of COX-2 has been linked to inflammation and carcinogenesis. Constitutive expression of COX-2 protects hepatocytes from several pro-apoptotic stimuli. Increased hepatic apoptosis has been observed in experimental models of diabetes. Our present aim was to analyze the role of COX-2 as a regulator of apoptosis in diabetic mouse liver. Mice of C57BL/6 strain wild type (Wt) and transgenic in COX-2 (hCOX-2 Tg) were separated into Control (vehicle) and SID (streptozotocin induced diabetes, 200 mg/kg body weight, i.p.). Seven days post-injection, Wt diabetic animals showed a decrease in PI3K activity and P-Akt levels, an increase of P-JNK, P-p38, pro-apoptotic Bad and Bax, release of cytochrome c and activities of caspases-3 and -9, leading to an increased apoptotic index. This situation was improved in diabetic COX-2 Tg. In addition, SID COX-2 Tg showed increased expression of anti-apoptotic Mcl-1 and XIAP. Pro-apoptotic state in the liver of diabetic animals was improved by over-expression of COX-2. We also analyzed the roles of high glucose-induced apoptosis and hCOX-2 in vitro. Non-transfected and hCOX-2-transfected cells were cultured at 5 and 25 mM of glucose by 72 h. At 25 mM there was an increase in apoptosis in non-transfected cells versus those exposed to 5 mM. This increase was partly prevented in transfected cells at 25 mM. Moreover, the protective effect observed in hCOX-2-transfected cells was suppressed by addition of DFU (COX-2 selective inhibitor), and mimicked by addition of PGE2 in non-transfected cells. Taken together, these results demonstrate that hyperglycemia-induced hepatic apoptosis is protected by hCOX-2 expression. J. Cell. Biochem. 114: 669–680, 2013. © 2012 Wiley Periodicals, Inc.

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