Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5'-monophosphate-dependent mechanism

Dongmin Liu; Laurie L Homan; Joseph S Dillon

doi:10.1210/en.2004-0102

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Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5'-monophosphate-dependent mechanism

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Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5'-monophosphate-dependent mechanism

Dongmin Liu, Laurie L Homan and Joseph S Dillon

Endocrinology (Philadelphia), Vol.145(12), pp.5532-5539

12/2004

DOI: 10.1210/en.2004-0102

PMID: 15319357

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Abstract

Genistein may improve vascular function, but the mechanism of this effect is unclear. We tested the hypothesis that genistein directly regulates vascular function through stimulation of endothelial nitric oxide synthesis. Genistein activated endothelial nitric oxide synthase (eNOS) in intact bovine aortic endothelial cells and human umbilical vein endothelial cells over an incubation period of 10 min. The maximal eNOS activity was at 1 microm genistein. Consistent with this activation pattern, 1 microm genistein maximally stimulated the phosphorylation of eNOS at serine 1179 at 10 min of incubation. The rapid activation of eNOS by genistein was not dependent on RNA transcription or new protein synthesis and was not blocked by a specific estrogen receptor antagonist. In addition, inhibition of MAPK or phosphatidylinositol 3-OH kinase/Akt kinase had no affect on eNOS activation by genistein. Furthermore, the genistein effect on eNOS was also independent of tyrosine kinase inhibition. However, inhibition of cAMP-dependent kinase [protein kinase A (PKA)] by H89 completely abolished the genistein-stimulated eNOS activation and phosphorylation, suggesting that genistein acted through a PKA-dependent pathway. These findings demonstrated that genistein had direct nongenomic effects on eNOS activity in vascular endothelial cells, leading to eNOS activation and nitric oxide synthesis. These effects were mediated by PKA and were unrelated to an estrogenic effect. This cellular mechanism may underlie some of the cardiovascular protective effects proposed for soy phytoestrogens.

Cyclic AMP-Dependent Protein Kinases - metabolism

Endothelium, Vascular - cytology

Proto-Oncogene Proteins - metabolism

Protein-Tyrosine Kinases - metabolism

Humans

Enzyme Inhibitors - pharmacology

Nitric Oxide Synthase Type III

Nitric Oxide Synthase - antagonists & inhibitors

Endothelium, Vascular - drug effects

Phosphatidylinositol 3-Kinases - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Endothelium, Vascular - enzymology

Proto-Oncogene Proteins c-akt

Animals

MAP Kinase Signaling System - drug effects

Cattle

Genistein - pharmacology

Nitric Oxide Synthase - metabolism

Aorta - cytology

Nitric Oxide - metabolism

Cyclic AMP - metabolism

Umbilical Veins - cytology

Protein-Serine-Threonine Kinases - metabolism

Details

Title: Subtitle: Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5'-monophosphate-dependent mechanism
Creators: Dongmin Liu - Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, Iowa 52246, USA
Laurie L Homan
Joseph S Dillon
Resource Type: Journal article
Publication Details: Endocrinology (Philadelphia), Vol.145(12), pp.5532-5539
DOI: 10.1210/en.2004-0102
PMID: 15319357
NLM abbreviation: Endocrinology
ISSN: 0013-7227
eISSN: 1945-7170
Grant note: AG55741 / NIA NIH HHS R01 AG018928 / NIA NIH HHS
Language: English
Date published: 12/2004
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094581202771

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