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Research ArticleCARDIOVASCULAR

The Ceiling Effect of Pharmacological Postconditioning with the Phytoestrogen Genistein Is Reversed by the GSK3β Inhibitor SB 216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through Mitochondrial ATP-Dependent Potassium Channel Opening

Nicolas Couvreur, Renaud Tissier, Sandrine Pons, Mourad Chenoune, Xavier Waintraub, Alain Berdeaux and Bijan Ghaleh
Journal of Pharmacology and Experimental Therapeutics June 2009, 329 (3) 1134-1141; DOI: https://doi.org/10.1124/jpet.109.152587
Nicolas Couvreur
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Renaud Tissier
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Sandrine Pons
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Mourad Chenoune
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Xavier Waintraub
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Alain Berdeaux
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Bijan Ghaleh
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Abstract

In the present study, we investigated the efficacy of pharmacological postconditioning induced by 17β-estradiol and the phytoestrogen, genistein, against myocardial infarction induced by increasing durations of coronary artery occlusion (CAO). Anesthetized rabbits underwent either 20-min (protocol A) or 30-min (protocol B) CAO, followed by 4 h of coronary artery reperfusion (CAR). Before CAR, they randomly received an intravenous injection of either vehicle (control), 100 or 1000 μg/kg genistein (Geni100 and Geni1000, respectively), or 100 μg/kg 17β-estradiol (17β-E100). In protocol A, infarct size was significantly reduced in Geni100 (n = 6), Geni1000 (n = 6), and 17β-E100 (n = 6) versus control (n = 9) (6 ± 2, 15 ± 4, and 11 ± 3 versus 35 ± 5%, respectively). In protocol B, none of these drugs reduced infarct size versus control. Western blots demonstrated an increase of Akt phosphorylation in the Geni100 and 17β-E100 hearts submitted to 20-min CAO but not to 30-min CAO. The selective GSK3β inhibitor SB 216763 (0.2 mg/kg) [3-(2,4)-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] did not exhibit cardioprotection at this dose, but its administration restored the cardioprotective effect of genistein and 17β-estradiol with 30-min CAO. Administration of 5-hydroxydecanoate (5 mg/kg) abolished the cardioprotective effects of Geni100 and 17β-E100 alone with 20-min CAO and also those observed when combined to SB 216763 with 30-min CAO. Thus, pharmacological postconditioning with genistein and 17β-estradiol is limited by a “ceiling effect of protection” along with a loss of Akt phosphorylation. However, this ceiling effect is reversed by concomitant inhibition of GSK3β by SB 216763 through opening of mitochondrial ATP-dependent potassium channels.

Footnotes

  • This work was supported by the French Agence Nationale pour la Recherche [Grant ANR-06-PHYSIO-Ischermdiol]; and “Fondation de l'Avenir” [Grant ET5-406].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.109.152587.

  • ABBREVIATIONS: PCD, postconditioning; KATP, ATP-dependent potassium; PI3K, phosphatidylinositol 3-kinase; SB 216763, 3-(2,4-dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione; CAO, coronary artery occlusion; 17β-E100,17β-estradiol (100 μg/kg); Geni100, genistein (100 μg/kg); Geni1000, genistein (1000 μg/kg); CAR, coronary artery reperfusion; 5-HD, 5-hydroxydecanoate.

    • Received February 20, 2009.
    • Accepted March 23, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 387 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 387, Issue 1
1 Oct 2023
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Research ArticleCARDIOVASCULAR

The Ceiling Effect of Pharmacological Postconditioning with the Phytoestrogen Genistein Is Reversed by the GSK3β Inhibitor SB 216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through Mitochondrial ATP-Dependent Potassium Channel Opening

Nicolas Couvreur, Renaud Tissier, Sandrine Pons, Mourad Chenoune, Xavier Waintraub, Alain Berdeaux and Bijan Ghaleh
Journal of Pharmacology and Experimental Therapeutics June 1, 2009, 329 (3) 1134-1141; DOI: https://doi.org/10.1124/jpet.109.152587

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Research ArticleCARDIOVASCULAR

The Ceiling Effect of Pharmacological Postconditioning with the Phytoestrogen Genistein Is Reversed by the GSK3β Inhibitor SB 216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through Mitochondrial ATP-Dependent Potassium Channel Opening

Nicolas Couvreur, Renaud Tissier, Sandrine Pons, Mourad Chenoune, Xavier Waintraub, Alain Berdeaux and Bijan Ghaleh
Journal of Pharmacology and Experimental Therapeutics June 1, 2009, 329 (3) 1134-1141; DOI: https://doi.org/10.1124/jpet.109.152587
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