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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Animals
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Carotid Artery Injuries / etiology
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Carotid Artery Injuries / physiopathology
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Catheterization
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Division / drug effects*
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Cells, Cultured
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Cilostazol
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Colforsin / pharmacology
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Cyclic AMP / metabolism
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DNA / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Down-Regulation*
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F2 Transcription Factor
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Humans
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Male
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Muscle, Smooth, Vascular / cytology*
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Myocytes, Smooth Muscle / cytology*
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Proliferating Cell Nuclear Antigen / metabolism
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Promoter Regions, Genetic
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Rats
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Rats, Sprague-Dawley
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Tetrazoles / administration & dosage
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Tetrazoles / pharmacology*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tunica Intima / drug effects
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Tunica Intima / growth & development
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2F1 protein, human
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E2F2 Transcription Factor
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E2F2 protein, human
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E2f1 protein, rat
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Proliferating Cell Nuclear Antigen
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Tetrazoles
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Transcription Factors
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Colforsin
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8-Bromo Cyclic Adenosine Monophosphate
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DNA
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Cyclic AMP
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Cilostazol