title: Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity.
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.
authors.affiliation: Whitaker Cardiovascular Institute, 700 Albany Street, Boston University School of Medicine, Boston, Massachusetts 02118, USA. jleopold@partners.org
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.forename: Aamir
authors.initials: A
authors.lastname: Dam
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Maron
authors.forename: Anne W
authors.initials: AW
authors.lastname: Scribner
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
authors.forename: Robert C
authors.initials: RC
authors.lastname: Stanton
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000704:Analysis of Variance; D015152:Blotting, Northern; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D000242:Cyclic AMP / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D018014:Gene Transfer Techniques; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology
chemical_list: C497410:CREM protein, human; D017931:DNA Primers; D000451:Mineralocorticoid Receptor Antagonists; D051786:Cyclic AMP Response Element Modulator; D013148:Spironolactone; D009569:Nitric Oxide; D000450:Aldosterone; D000242:Cyclic AMP; D005954:Glucosephosphate Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases