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Phytoestrogen genistein up‐regulates endothelial nitric oxide synthase expression via activation of cAMP‐responsive element‐binding protein in human aortic endothelial cells
Author(s) -
Liu Dongmin,
Si Hongwei,
Jiang Hongling
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.112.2
Subject(s) - genistein , enos , creb , protein kinase b , protein kinase a , phosphorylation , chemistry , nitric oxide synthase type iii , microbiology and biotechnology , nitric oxide synthase , nitric oxide , medicine , biology , endocrinology , biochemistry , transcription factor , gene
We previously reported that genistein up‐regulates endothelial nitric oxide synthase (eNOS) and prevents hypertension in rats. However, how genistein regulates eNOS expression is unknown. Here, we show that genistein enhanced eNOS expression and nitric oxide (NO) synthesis in human aortic endothelial cells (HAECs). Inhibition of mitogen‐activated protein kinase, phosphatidylinositol 3‐OH kinase/Akt, or protein kinase C did not affect genistein‐enhanced NO synthesis. In addition, blockage of estrogen or prostanoid receptors failed to inhibit genistein‐stimulated eNOS expression. However, chemical or genetic inhibition of protein kinase A (PKA) completely abolished genistein‐stimulated eNOS expression and NO production in HAECs. Accordingly, genistein induced PKA activity and subsequent phosphorylation of cAMP‐responsive element‐binding protein (CREB). Suppression of CREB by siRNA transfection abolished genistein‐enhanced eNOS expression and NO production. Consistently, deletion of the cAMP responsive‐element (CRE) site within human eNOS promoter eliminated genistein‐stimulated eNOS promoter activity. These findings provide the first evidence that genistein directly targets cAMP/PKA/CREB/eNOS/NO signaling in ECs. This work was supported by grants from the AHA Mid‐Atlantic Affiliate (to DL) and the NCCAM of NIH (1R21AT004694 and 1R21AT002739 to DL).