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         headline:Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity
         description: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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      description: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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            address:
               name:Whitaker Cardiovascular Institute
               type:PostalAddress
            type:Organization
            name:Boston University School of Medicine
            address:
               name:Boston University School of Medicine, Boston, USA
               type:PostalAddress
            type:Organization
      name:Ronglih Liao
      affiliation:
            name:Whitaker Cardiovascular Institute
            address:
               name:Whitaker Cardiovascular Institute
               type:PostalAddress
            type:Organization
            name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
            address:
               name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
               type:PostalAddress
            type:Organization
            name:Boston University School of Medicine
            address:
               name:Boston University School of Medicine, Boston, USA
               type:PostalAddress
            type:Organization
      name:Diane E Handy
      affiliation:
            name:Whitaker Cardiovascular Institute
            address:
               name:Whitaker Cardiovascular Institute
               type:PostalAddress
            type:Organization
            name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
            address:
               name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
               type:PostalAddress
            type:Organization
            name:Boston University School of Medicine
            address:
               name:Boston University School of Medicine, Boston, USA
               type:PostalAddress
            type:Organization
      name:Robert C Stanton
      affiliation:
            name:Renal Section, Joslin Diabetes Center, 1 Joslin Place, Harvard Medical School
            address:
               name:Renal Section, Joslin Diabetes Center, 1 Joslin Place, Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
      name:Bertram Pitt
      affiliation:
            name:University of Michigan School of Medicine, Taubman Medical Center
            address:
               name:Division of Cardiology, University of Michigan School of Medicine, Taubman Medical Center, Ann Arbor, USA
               type:PostalAddress
            type:Organization
      name:Joseph Loscalzo
      affiliation:
            name:Whitaker Cardiovascular Institute
            address:
               name:Whitaker Cardiovascular Institute
               type:PostalAddress
            type:Organization
            name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
            address:
               name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
               type:PostalAddress
            type:Organization
            name:Boston University School of Medicine
            address:
               name:Boston University School of Medicine, Boston, USA
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Whitaker Cardiovascular Institute
      name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
      name:Boston University School of Medicine, Boston, USA
      name:Whitaker Cardiovascular Institute
      name:Boston University School of Medicine, Boston, USA
      name:Whitaker Cardiovascular Institute
      name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
      name:Boston University School of Medicine, Boston, USA
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      name:Boston University School of Medicine, Boston, USA
      name:Whitaker Cardiovascular Institute
      name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
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      name:Renal Section, Joslin Diabetes Center, 1 Joslin Place, Harvard Medical School, Boston, USA
      name:Division of Cardiology, University of Michigan School of Medicine, Taubman Medical Center, Ann Arbor, USA
      name:Whitaker Cardiovascular Institute
      name:Present address: Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.,
      name:Boston University School of Medicine, Boston, USA
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