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

被引：7
作者：
Chen, Wei-Jan [1 ,5 ]
Chen, Ying-Hwa [2 ]
Lai, Ying-Ju [3 ]
Hsu, Yu-Juei [4 ]
Yeh, Yung-Hsin [1 ]
Tsai, Chien-Sung [5 ]
Lin, Chih-Yuan [5 ]
机构：
[1] Chang Gung Univ, Chang Gung Mem Hosp, Coll Med, Dept Internal Med,Div Cardiol, Taoyuan, Taiwan
[2] Natl Yang Ming Univ, Taipei Vet Gen Hosp, Coll Med, Dept Internal Med,Div Cardiol, Taipei, Taiwan
[3] Chang Gung Univ, Dept Resp Therapy, Taoyuan, Taiwan
[4] Natl Def Med Ctr, Triserv Gen Hosp, Dept Internal Med, Div Nephrol, Taipei, Taiwan
[5] Natl Def Med Ctr, Triserv Gen Hosp, Dept Surg, Div Cardiovasc Surg, Taipei, Taiwan
来源：
INTERNATIONAL JOURNAL OF CARDIOLOGY | 2016年 / 222卷
关键词：
Cilostazol; CREB; Heme oxygenase-1; Polymorphism; Vascular smooth muscle cells; ATHEROSCLEROTIC LESION FORMATION; MICROSATELLITE POLYMORPHISM; INTERMITTENT CLAUDICATION; NEOINTIMAL FORMATION; BALLOON INJURY; GENE PROMOTER; RESTENOSIS; SUSCEPTIBILITY; ANGIOPLASTY; EXPRESSION;
D O I：
10.1016/j.ijcard.2016.07.234
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码：407 / 415
页数：9
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