Cilostazol inhibits cytokine-induced tetrahydrobiopterin biosynthesis in human umbilical vein endothelial cells.

Hiroaki Shiraishi, Kazuhisa Ikemoto, Shin Tada, Yasuhiro Udagawa, Masatsugu Ohtsuki, Chiho Sumi-Ichinose, Kazunao Kondo, Takahide Nomura

研究成果: ジャーナルへの寄稿学術論文査読

5 被引用数 (Scopus)


Cilostazol, a type III phosphodiesterase inhibitor, is utilized for the treatment of intermittent claudication and is considered to have the beneficial effects against the atherogenic process. In the present study, we examined the effects of cilostazol on BH(4) biosynthesis in HUVEC treated with a mixture of the pro-inflammatory cytokines IFN-γ and TNF-α. Isolated HUVECs were grown to confluence and treated with IFN-γ (300 units/mL) and TNF-α (300 units/mL) for 16 h in order to stimulate BH(4) biosynthesis. The BH(4) levels were measured by HPLC. The mRNA expression of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH(4) biosynthesis, and GTPCH feedback regulatory protein (GFRP) were quantified by real-time PCR. The GTPCH protein expression was assessed by western blot analysis. Cilostazol significantly reduced the BH(4) levels in cytokine-stimulated HUVEC. Cilostazol produced a concomitant increase in the cAMP levels in HUVEC. Cilostazol decreased the GTPCH activity as well as the expression of GTPCH mRNA and protein. 8-bromo-cAMP (8Br-cAMP), a cell-permeable cAMP analogue, did not reproduce the effects of cilostazol. Cilostazol did not affect the cytokine-induced inhibition of GFRP mRNA expression. We conclude that cilostazol inhibited cytokine-stimulated BH(4) biosynthesis via a cAMP-independent mechanism in HUVEC. Our data indicate that cilostazol reduced GTPCH activity and did so by suppressing the GTPCH protein levels.

ジャーナルJournal of atherosclerosis and thrombosis
出版ステータス出版済み - 27-04-2011

All Science Journal Classification (ASJC) codes

  • 内科学
  • 循環器および心血管医学
  • 生化学、医学


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