UNLABELLED: Estrogen is associated with increased heat shock protein (HSP)72 and protection during hypoxia-reoxygenation in cardiomyocytes from adult male rats, as previously reported. We have also reported that female rats have more cardiac HSP72 than males. We hypothesized that, despite higher endogenous estrogen levels and higher baseline HSP72, 17 beta-estradiol treatment would still result in increased HSP72 and protection during hypoxia-reoxygenation in cardiomyocytes from females. METHODS/ RESULTS: Cardiac cells isolated from adult female rats were treated for 12 hr with 17 beta-estradiol (0.1, 10, or 50 microM), tamoxifen, (10 or 25 microM; estrogen receptor agonist/antagonist), geldanamycin (2, 5, or 10 microg/ml; inactivates HSP90, preventing interaction with HSF1), or vehicle. Western blot analyses revealed that treatment with 17 beta-estradiol (10 or 50 microM), tamoxifen (25 microM), and geldanamycin (all doses) resulted in significant increases in HSP72. Electromobility shift assays revealed activation of HSF1 by 2 to 3 hr, and NF kappa B activation by 15 min. HSP72 induction via HSF1 activation was confirmed using transcription factor decoys containing the heat shock element, which prevented the estrogen-related HSP72 induction. Estrogen pretreatment resulted in decreased LDH release during 24 hr hypoxia. This protective effect persisted despite decoy-mediated blockade of nuclear HSF1 binding. However, transfection with an NF?B decoy not only prevented an estrogen-associated increase in HSP72, but also abolished the estrogen-related protection during hypoxia. CONCLUSIONS: Despite higher endogenous estrogen, 17 beta-estradiol and the selective estrogen receptor modulator, tamoxifen, upregulate HSP72 in cardiomyocytes from adult females, and provide cytoprotection during hypoxia, independent of HSP induction. NF kappa B activation is necessary for the increase in HSP72, suggesting that estrogen treatment activates NF kappa B, with subsequent HSF1 activation. NF kappa B activation is critical for estrogen-associated HSP induction, and protection during hypoxia in female cardiocytes. Treatment with 17 beta-estradiol and tamoxifen may provide a novel means of protecting both male and female cardiac myocytes against hypoxia-induced damage. Further studies are needed to define the cross-talk between HSF1 and NF kappa B signaling pathways.
UNLABELLED: Estrogen is associated with increased heat shock protein (HSP)72 and protection during hypoxia-reoxygenation in cardiomyocytes from adult male rats, as previously reported. We have also reported that female rats have more cardiac HSP72 than males. We hypothesized that, despite higher endogenous estrogen levels and higher baseline HSP72, 17 beta-estradiol treatment would still result in increased HSP72 and protection during hypoxia-reoxygenation in cardiomyocytes from females. METHODS/ RESULTS: Cardiac cells isolated from adult female rats were treated for 12 hr with 17 beta-estradiol (0.1, 10, or 50 microM), tamoxifen, (10 or 25 microM; estrogen receptor agonist/antagonist), geldanamycin (2, 5, or 10 microg/ml; inactivates HSP90, preventing interaction with HSF1), or vehicle. Western blot analyses revealed that treatment with 17 beta-estradiol (10 or 50 microM), tamoxifen (25 microM), and geldanamycin (all doses) resulted in significant increases in HSP72. Electromobility shift assays revealed activation of HSF1 by 2 to 3 hr, and NF kappa B activation by 15 min. HSP72 induction via HSF1 activation was confirmed using transcription factor decoys containing the heat shock element, which prevented the estrogen-related HSP72 induction. Estrogen pretreatment resulted in decreased LDH release during 24 hr hypoxia. This protective effect persisted despite decoy-mediated blockade of nuclear HSF1 binding. However, transfection with an NF?B decoy not only prevented an estrogen-associated increase in HSP72, but also abolished the estrogen-related protection during hypoxia. CONCLUSIONS: Despite higher endogenous estrogen, 17 beta-estradiol and the selective estrogen receptor modulator, tamoxifen, upregulate HSP72 in cardiomyocytes from adult females, and provide cytoprotection during hypoxia, independent of HSP induction. NF kappa B activation is necessary for the increase in HSP72, suggesting that estrogen treatment activates NF kappa B, with subsequent HSF1 activation. NF kappa B activation is critical for estrogen-associated HSP induction, and protection during hypoxia in female cardiocytes. Treatment with 17 beta-estradiol and tamoxifen may provide a novel means of protecting both male and female cardiac myocytes against hypoxia-induced damage. Further studies are needed to define the cross-talk between HSF1 and NF kappa B signaling pathways.
Authors: Angela S Pechenino; Li Lin; Fiona N Mbai; Alison R Lee; Xian-Min He; John N Stallone; A A Knowlton Journal: Physiol Genomics Date: 2011-07-12 Impact factor: 3.107
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