Cilostazol promotes vascular smooth muscles cell differentiation through the cAMP response element-binding protein-dependent pathway

Wei Jan Chen*, Ying Hwa Chen, Kwang Huei Lin, Chiao Hsuan Ting, Yung Hsin Yeh

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

48 Scopus citations

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. Methods and 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. Conclusion-: Cilostazol promotes VSMC differentiation through the cAMP/PKA/CREB signaling cascade.

Original languageEnglish
Pages (from-to)2106-2113
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume31
Issue number9
DOIs
StatePublished - 09 2011

Keywords

  • CREB
  • cilostazol
  • differentiation
  • neointimal formation
  • vascular smooth muscle cells

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