Abstract
Hyperaldosteronism is associated with impaired vascular reactivity; however, the mechanisms by which aldosterone promotes endothelial dysfunction remain unknown. Glucose-6-phosphate dehydrogenase (G6PD) modulates vascular function by limiting oxidant stress to preserve bioavailable nitric oxide (NO•). Here we show that aldosterone (10−9–;10−7 mol/l) decreased endothelial G6PD expression and activity in vitro, resulting in increased oxidant stress and decreased NO• levels—similar to what is observed in G6PD-deficient endothelial cells. Aldosterone decreased G6PD expression by increasing expression of the cyclic AMP−response element modulator (CREM) to inhibit cyclic AMP−response element binding protein (CREB)-mediated G6PD transcription. In vivo, infusion of aldosterone decreased vascular G6PD expression and impaired vascular reactivity. These effects were abrogated by spironolactone or vascular gene transfer of G6pd. These findings demonstrate that aldosterone induces a G6PD-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6PD activity.
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Change history
04 September 2009
In the version of this article initially published, the number of one of the grants listed in the Acknowledgments was incorrect; ‘HL55993’ should have been ‘P01 HL81587’. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
This work was supported in part by the US National Institutes of Health (grants HL61828, HL58976, P01 HL81587, HV28178 to J.L.; HL04399 and HL081110 to J.A.L.; HL067297, HL071775 and HL073756 to R.L.; and DK053480-05 to R.C.S.) and by a Grant-in-Aid from the American Heart Association (to J.A.L.).
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Contributions
J.A.L. designed the study, supervised the project, conducted experiments and wrote the manuscript. A.D. contributed to the in vitro and in vivo experiments. B.A.M., A.W.S., D.E.H. and R.C.S contributed to the in vitro experiments. R.L. contributed to the in vivo experiments. B.P. contributed to data interpretation. J.L. contributed to data interpretation and manuscript critique.
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B.P. is a consultant for Pfizer, Novartis, Alteon and Astra Zeneca.
Supplementary information
Supplementary Fig. 1
Aldosterone decreases G6PD expression in human coronary artery endothelial cells. (PDF 47 kb)
Supplementary Fig. 2
Aldosterone decreases G6PD expression by protein kinase A activation. (PDF 56 kb)
Supplementary Fig. 3
Inhibition of CREB or CREM expression by siRNA. (PDF 68 kb)
Supplementary Fig. 4
Aldosterone and CREB activation: upstream signaling kinases and downstream transcription factors. (PDF 73 kb)
Supplementary Fig. 5
Source of reactive oxygen species in aldosterone-treated cells. (PDF 43 kb)
Supplementary Fig. 6
Spironolactone increases G6PD activity. (PDF 28 kb)
Supplementary Fig. 7
G6PD overexpression preserves G6PD activity in vitro. (PDF 49 kb)
Supplementary Fig. 8
G6PD overexpression preserves G6PD activity in vivo. (PDF 52 kb)
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Leopold, J., Dam, A., Maron, B. et al. Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. Nat Med 13, 189–197 (2007). https://doi.org/10.1038/nm1545
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DOI: https://doi.org/10.1038/nm1545
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