title: Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F.
abstract: Neointimal formation, the leading cause of restenosis, is caused by proliferation of vascular smooth muscle cells (VSMCs). Patients with diabetes mellitus have higher restenosis rates after coronary angioplasty than nondiabetic patients. Cilostazol, a selective type 3 phosphodiesterase inhibitor, is currently used to treat patients with diabetic vascular complications. Cilostazol is a potent antiplatelet agent that inhibits VSMC proliferation. In the present study, we examine whether the antiproliferative effect of cilostazol on VSMCs is mediated by inhibition of an important cell cycle transcription factor, E2F. Cilostazol inhibited the proliferation of human VSMCs in response to high glucose in vitro and virtually abolished neointimal formation in rats subjected to carotid artery injury in vivo. Moreover, the compound suppressed high-glucose-induced E2F-DNA binding activity, and the expression of E2F1, E2F2, cyclin A, and PCNA proteins. These data suggest that the beneficial effects of cilostazol on high-glucose-stimulated proliferation of VSMCs are mediated by the downregulation of E2F activity and expression of its downstream target genes, including E2F1, E2F2, cyclin A, and PCNA.
authors.affiliation: Department of Internal Medicine, Keimyung University School of Medicine, Daegu, South Korea.
authors.forename: Mi-Jung
authors.initials: MJ
authors.lastname: Kim
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: Kyeong-Min
authors.initials: KM
authors.lastname: Lee
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Kim
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Chun-Soo
authors.initials: CS
authors.lastname: Kim
authors.forename: Sang-Lak
authors.initials: SL
authors.lastname: Lee
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D020212:Carotid Artery Injuries / Q000209:etiology / Q000503:physiopathology; D002404:Catheterization; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D000077407:Cilostazol; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000254:growth & development
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; C493755:E2f1 protein, rat; D018809:Proliferating Cell Nuclear Antigen; D013777:Tetrazoles; D014157:Transcription Factors; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004247:DNA; D000242:Cyclic AMP; D000077407:Cilostazol