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

      1 , , ,
      Atherosclerosis
      Elsevier BV

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          Abstract

          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.

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          Author and article information

          Journal
          Atherosclerosis
          Atherosclerosis
          Elsevier BV
          0021-9150
          0021-9150
          Dec 2006
          : 189
          : 2
          Affiliations
          [1 ] Research Institute of Pharmacological & Therapeutical Development, Otsuka Pharmaceutical Co. Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
          Article
          S0021-9150(06)00050-5
          10.1016/j.atherosclerosis.2006.01.022
          16545819
          67cc3c5f-9f43-472e-be51-262687916bc3
          History

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