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Evidence for a Possible Inhibitory Interaction between the HO-1/CO- and Akt/NO-Pathways in Human Endothelial Cells

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Abstract

Objective

The protective properties of heme oxygenase 1 (HO-1) give reason to study this mechanism as a potential therapeutic target for inflammatory and cardiovascular diseases. Recent evidence suggests a possible interaction between the HO-1/CO- and the protein kinase Akt/NO-pathway. This study was designed to examine the effects of continuous HO-1 overexpression in endothelial cells.

Methods

Oncoretroviral vectors were constructed to achieve constitutive overexpression of HO-1, Akt, and green fluorescence protein in human umbilical vein endothelial cells. [3H]thymidine-incorporation and lipid-peroxidation were measured following exposure to heme and H2O2. Expression of HO-1, Akt and its downstream-target endothelial NO-synthase were quantified by Western blot analysis. NO-synthase-activity was measured using the citrulline-conversion-assay.

Results

HO-1-overexpression reduced proliferative rates and DNA-synthesis of HUVEC, but provided potent protection from oxidative stress induced by heme and H2O2. Phosphorylated-Akt and eNOS was downregulated in HO-1-HUVEC. eNOS-activity was reduced in HO-1-HUVEC. Co-infection with the Akt-retrovirus restored proliferative rates and eNOS-expression and -activity.

Conclusion

Continuously elevated HO-1-activity protects EC from oxidative stress but inhibits Akt-mediated proliferation and eNOS-expression. This inhibitory feedback mechanism could be a limitation of HO-1 as a target for the treatment of vascular disease.

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Authors and Affiliations

  1. Department of Internal Medicine II, Regensburg University Medical Center, Franz Josef Strauss Allee 11, 93053, Regensburg, Germany

    Christian A. Batzlsperger, Stefan Achatz, Josefine Spreng, Guenter A. J. Riegger & Daniel P. Griese

Authors
  1. Christian A. Batzlsperger
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  2. Stefan Achatz
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  3. Josefine Spreng
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  4. Guenter A. J. Riegger
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  5. Daniel P. Griese
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Corresponding author

Correspondence to Daniel P. Griese.

Additional information

Christian A. Batzlsperger and Stefan Achatz contributed equally to this work.

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Batzlsperger, C.A., Achatz, S., Spreng, J. et al. Evidence for a Possible Inhibitory Interaction between the HO-1/CO- and Akt/NO-Pathways in Human Endothelial Cells. Cardiovasc Drugs Ther 21, 347–355 (2007). https://doi.org/10.1007/s10557-007-6051-1

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  • DOI: https://doi.org/10.1007/s10557-007-6051-1

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