GT-repeat length polymorphism in heme oxygenase-1 promoter determines the effect of cilostazol on vascular smooth muscle cells
Copyright policy )GT-repeat length polymorphism in heme oxygenase-1 promoter determines the effect of cilostazol on vascular smooth muscle cells
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).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.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.
- Tri-Service General Hospital Taiwan
- Taipei Veterans General Hospital Taiwan
- Chang Gung Memorial Hospital Taiwan
- National Defense Medical Center Taiwan
- Chang Gung University Taiwan
Male, Polymorphism, Genetic, Dose-Response Relationship, Drug, Myocytes, Smooth Muscle, Tetrazoles, Phosphodiesterase 3 Inhibitors, Muscle, Smooth, Vascular, Cilostazol, Rats, Treatment Outcome, Animals, Humans, Rats, Wistar, Promoter Regions, Genetic, Cells, Cultured, Heme Oxygenase-1, Cell Proliferation
Male, Polymorphism, Genetic, Dose-Response Relationship, Drug, Myocytes, Smooth Muscle, Tetrazoles, Phosphodiesterase 3 Inhibitors, Muscle, Smooth, Vascular, Cilostazol, Rats, Treatment Outcome, Animals, Humans, Rats, Wistar, Promoter Regions, Genetic, Cells, Cultured, Heme Oxygenase-1, Cell Proliferation
selected citations These citations are derived from selected sources.This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).9 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average
Citations provided by BIP!Popularity provided by BIP!