Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity. 2007

Jane A Leopold, and Aamir Dam, and Bradley A Maron, and Anne W Scribner, and Ronglih Liao, and Diane E Handy, and Robert C Stanton, and Bertram Pitt, and Joseph Loscalzo
Whitaker Cardiovascular Institute, 700 Albany Street, Boston University School of Medicine, Boston, Massachusetts 02118, USA. jleopold@partners.org

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.

UI MeSH Term Description Entries
D009569 Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP. Endogenous Nitrate Vasodilator,Mononitrogen Monoxide,Nitric Oxide, Endothelium-Derived,Nitrogen Monoxide,Endothelium-Derived Nitric Oxide,Monoxide, Mononitrogen,Monoxide, Nitrogen,Nitrate Vasodilator, Endogenous,Nitric Oxide, Endothelium Derived,Oxide, Nitric,Vasodilator, Endogenous Nitrate
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004730 Endothelium, Vascular Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components. Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D005954 Glucosephosphate Dehydrogenase Glucose-6-Phosphate Dehydrogenase,Dehydrogenase, Glucose-6-Phosphate,Dehydrogenase, Glucosephosphate,Glucose 6 Phosphate Dehydrogenase
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000242 Cyclic AMP An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH. Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000450 Aldosterone A hormone secreted by the ADRENAL CORTEX that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Aldosterone, (+-)-Isomer,Aldosterone, (11 beta,17 alpha)-Isomer
D000451 Mineralocorticoid Receptor Antagonists Drugs that bind to and block the activation of MINERALOCORTICOID RECEPTORS by MINERALOCORTICOIDS such as ALDOSTERONE. Aldosterone Antagonist,Aldosterone Antagonists,Aldosterone Receptor Antagonist,Mineralocorticoid Antagonist,Mineralocorticoid Receptor Antagonist,Aldosterone Receptor Antagonists,Mineralocorticoid Antagonists,Antagonist, Aldosterone,Antagonist, Aldosterone Receptor,Antagonist, Mineralocorticoid,Antagonist, Mineralocorticoid Receptor,Antagonists, Aldosterone,Antagonists, Aldosterone Receptor,Antagonists, Mineralocorticoid,Antagonists, Mineralocorticoid Receptor,Receptor Antagonist, Aldosterone,Receptor Antagonist, Mineralocorticoid,Receptor Antagonists, Aldosterone,Receptor Antagonists, Mineralocorticoid
D000704 Analysis of Variance A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable. ANOVA,Analysis, Variance,Variance Analysis,Analyses, Variance,Variance Analyses
D013148 Spironolactone A potassium sparing diuretic that acts by antagonism of aldosterone in the distal renal tubules. It is used mainly in the treatment of refractory edema in patients with congestive heart failure, nephrotic syndrome, or hepatic cirrhosis. Its effects on the endocrine system are utilized in the treatments of hirsutism and acne but they can lead to adverse effects. (From Martindale, The Extra Pharmacopoeia, 30th ed, p827) Spirolactone,Aldactone,Aldactone A,Aquareduct,Duraspiron,Espironolactona Alter,Espironolactona Mundogen,Flumach,Frumikal,Jenaspiron,Novo-Spiroton,Practon,SC-9420,Spiractin,Spiro L.U.T.,Spiro Von Ct,Spirobeta,Spirogamma,Spirolang,Spirono-Isis,Spironone,Spirospare,Veroshpiron,Verospiron,Verospirone,Ct, Spiro Von,Novo Spiroton,NovoSpiroton,SC 9420,SC9420,Spirono Isis,Von Ct, Spiro

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