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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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.).
B.P. is a consultant for Pfizer, Novartis, Alteon and Astra Zeneca.
Aldosterone decreases G6PD expression in human coronary artery endothelial cells. (PDF 47 kb)
Aldosterone decreases G6PD expression by protein kinase A activation. (PDF 56 kb)
Inhibition of CREB or CREM expression by siRNA. (PDF 68 kb)
Aldosterone and CREB activation: upstream signaling kinases and downstream transcription factors. (PDF 73 kb)
Source of reactive oxygen species in aldosterone-treated cells. (PDF 43 kb)
Spironolactone increases G6PD activity. (PDF 28 kb)
G6PD overexpression preserves G6PD activity in vitro. (PDF 49 kb)
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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