Article abstract
Nature Medicine 13, 189 - 197 (2007)
Published online: 4 February 2007 | Corrected online: 4 September 2009 | doi:10.1038/nm1545
There is a Corrigendum (September 2009) associated with this Article.
Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity
Jane A Leopold1,4, Aamir Dam1, Bradley A Maron1,4, Anne W Scribner1, Ronglih Liao1,4, Diane E Handy1,4, Robert C Stanton2, Bertram Pitt3 & Joseph Loscalzo1,4
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)-mediatedG6PD 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.
- Whitaker Cardiovascular Institute, 700 Albany Street, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
- Renal Section, Joslin Diabetes Center, 1 Joslin Place, Harvard Medical School, Boston, Massachusetts 02215, USA.
- Division of Cardiology, University of Michigan School of Medicine, Taubman Medical Center, 1500 E Medical Center Drive, Ann Arbor, Michigan 48109, USA.
- Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Correspondence to: Jane A Leopold1,4 e-mail: jleopold@partners.org
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