GT-repeat length polymorphism in heme oxygenase-1 promoter determines the effect of cilostazol on vascular smooth muscle cells

Wei Jan Chen*, Ying Hwa Chen, Ying Ju Lai, Yu Juei Hsu, Yung Hsin Yeh, Chien Sung Tsai, Chih Yuan Lin

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

7 Scopus citations

Abstract

Background Cilostazol, a potent type 3 phosphodiesterase inhibitor, is found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether the inhibitory effect of cilostazol on VSMC proliferation is operated via heme oxygenase-1 (HO-1). Methods and results In rat carotid arteries, cilostazol up-regulated HO-1 in the neointima of balloon-injured arteries. Treatment of human VSMCs with cilostazol enhanced the expression of HO-1, which was mainly regulated at the transcriptional level. Small interfering RNA knock-down of HO-1 attenuated the inhibitory effect of cilostazol on VSMC proliferation, suggesting the critical role of HO-1 in cilostazol effect. The transcriptional responsiveness of HO-1 to cilostazol was inversely correlated with the length of GT-repeat in human HO-1 promoter. Deletion and mutational analysis of HO-1 promoter along with chromatin immunoprecipitation showed that cyclic AMP response element (CRE)-binding protein (CREB) participated in cilostazol-induced HO-1 transcription. Furthermore, cilostazol triggered a linkage between the CRE and GT-repeat regions in the HO-1 promoter. The promoting effect of cilostazol on HO-1 expression, proliferation inhibition, and chromatin conformation in the HO-1 promoter was greater in VSMCs from subjects with shorter GT-repeat alleles than those with longer alleles. Conclusions Cilostazol inhibits VSMC proliferation involving an association between CREB and HO-1. The length polymorphism of GT-repeat in human HO-1 promoter determines the effect of cilostazol.

Original languageEnglish
Pages (from-to)407-415
Number of pages9
JournalInternational Journal of Cardiology
Volume222
DOIs
StatePublished - 01 11 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Ireland Ltd

Keywords

  • CREB
  • Cilostazol
  • Heme oxygenase-1
  • Polymorphism
  • Vascular smooth muscle cells

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