title: GT-repeat length polymorphism in heme oxygenase-1 promoter determines the effect of cilostazol on vascular smooth muscle cells.
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).
  
  
  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.
authors: Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan. Electronic address: wjchen@adm.cgmh.org.tw.
authors: Wei-Jan
authors: WJ
authors: Chen
authors: Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, National Yang-Ming University College of Medicine, Taipei, Taiwan.
authors: Ying-Hwa
authors: YH
authors: Chen
authors: Department of Respiratory Therapy, Chang Gung University, Tao-Yuan, Taiwan.
authors: Ying-Ju
authors: YJ
authors: Lai
authors: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Yu-Juei
authors: YJ
authors: Hsu
authors: Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan.
authors: Yung-Hsin
authors: YH
authors: Yeh
authors: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Chien-Sung
authors: CS
authors: Tsai
authors: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Chih-Yuan
authors: CY
authors: Lin
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D000077407:Cilostazol; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D051547:Heme Oxygenase-1; D000077407:Cilostazol
keywords: CREB; Cilostazol; Heme oxygenase-1; Polymorphism; Vascular smooth muscle cells