title: Cilostazol promotes vascular smooth muscles cell differentiation through the cAMP response element-binding protein-dependent pathway.
abstract: OBJECTIVE
  Cilostazol, a potent type 3 phosphodiesterase inhibitor, has recently been found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether cilostazol exerts an action on phenotypic modulation of VSMCs, another important process in the pathogenesis of neointimal formation.
  
  
  RESULTS
  Cilostazol may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of smooth muscle cell differentiation marker contractile proteins. The upregulation of contractile proteins by cilostazol involves the cAMP/protein kinase A (PKA) signaling pathway, because the cAMP analog mimicked and specific cAMP/PKA inhibitors opposed the effect of cilostazol. Furthermore, cilostazol-activated cAMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Deletion and mutational analysis of the contractile protein promoters along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE is essential for cilostazol-induced contractile protein expression. Transfection of dominant-negative CREB (mutated Ser133) plasmid in VSMCs blocked cilostazol-stimulated contractile protein expression. In vivo, cilostazol upregulated contractile proteins and induced the activation of CREB in the neointima of balloon-injured arteries.
  
  
  CONCLUSIONS
  Cilostazol promotes VSMC differentiation through the cAMP/PKA/CREB signaling cascade.
authors.affiliation: First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Tao-Yuan, Taiwan. wjchen@adm.cgmh.org.tw
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
authors.forename: Ying-Hwa
authors.initials: YH
authors.lastname: Chen
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
authors.forename: Chiao Hsuan
authors.initials: CH
authors.lastname: Ting
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000077407:Cilostazol; D003285:Contractile Proteins / Q000096:biosynthesis; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D058426:Neointima / Q000209:etiology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D003285:Contractile Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000077407:Cilostazol