Activation of endothelial nitric oxide synthase by cilostazol via a cAMP/protein kinase A- and phosphatidylinositol 3-kinase/Akt-dependent mechanism

We investigated the effect of cilostazol on nitric oxide (NO) production in human aortic endothelial cells (HAEC). Cilostazol increased NO production in a concentration-dependent manner, and NO production was also increased by other cyclic-AMP (cAMP)-elevating agents (forskolin, cilostamide, and rol...

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Bibliographic Details
Published in:Atherosclerosis 2006-12, Vol.189 (2), p.350-357
Main Authors: Hashimoto, Ayako, Miyakoda, Goro, Hirose, Yoshimi, Mori, Toyoki
Format: Article
Language:English
Subjects:
Akt
Aorta - cytology
Aorta - drug effects
Aorta - enzymology
Associated diseases and complications
Atherosclerosis (general aspects, experimental research)
Biological and medical sciences
Blood and lymphatic vessels
Blotting, Western
Cardiology. Vascular system
Cell Division - drug effects
Cells, Cultured
Chromones - pharmacology
Cilostazol
Coronary heart disease
Cyclic AMP-Dependent Protein Kinases - drug effects
Cyclic AMP-Dependent Protein Kinases - metabolism
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Endothelial cells
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
eNOS
Enzyme Activation
Enzyme Inhibitors - pharmacology
Heart
Humans
Medical sciences
Morpholines - pharmacology
Neovascularization, Physiologic - drug effects
Neovascularization, Physiologic - physiology
NG-Nitroarginine Methyl Ester - pharmacology
Nitric oxide
Nitric Oxide Synthase Type III - drug effects
Nitric Oxide Synthase Type III - metabolism
Phosphatidylinositol 3-Kinases - drug effects
Phosphatidylinositol 3-Kinases - metabolism
Phosphodiesterase Inhibitors - pharmacology
Phosphorylation - drug effects
PKA
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Tetrazoles - pharmacology
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Summary:We investigated the effect of cilostazol on nitric oxide (NO) production in human aortic endothelial cells (HAEC). Cilostazol increased NO production in a concentration-dependent manner, and NO production was also increased by other cyclic-AMP (cAMP)-elevating agents (forskolin, cilostamide, and rolipram). Cilostazol increased intracellular cAMP level, and that effect was enhanced in the presence of forskolin. In Western blot analysis, cilostazol increased phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser 1177 and of Akt at Ser 473 and dephosphorylation of eNOS at Thr 495. Cilostazol's regulation of eNOS phosphorylation was reversed by protein kinase A inhibitor peptide (PKAI) and by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. Moreover, the cilostazol-induced increase in NO production was inhibited by PKAI, LY294002, and N G-nitro- l-arginine methyl ester hydrochloride ( l-NAME), a NOS inhibitor. In an in vitro model of angiogenesis, cilostazol-enhanced endothelial tube formation, an effect that was completely attenuated by inhibitors of PKA, PI3K, and NOS. These results suggest that cilostazol induces NO production by eNOS activation via a cAMP/PKA- and PI3K/Akt-dependent mechanism and that this effect is involved in capillary-like tube formation in HAEC.
ISSN:0021-9150
1879-1484
DOI:10.1016/j.atherosclerosis.2006.01.022