Abstract
Increased expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues is a potential factor linking diabetes to restenosis after percutaneous coronary intervention. Recent studies have shown that cilostazol, a selective type 3 phosphodiesterase inhibitor, prevents neointimal hyperplasia and in-stent thrombosis in patients with diabetes after coronary angioplasty and stent implantation. However, the molecular mechanism of this drug has not been fully elucidated. We examined whether cilostazol inhibits PAI-1 expression in vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. We found that cilostazol effectively inhibits angiotensin II-, high glucose- and TGF-beta-stimulated PAI-1 expression in vivo and in vitro. Cilostazol attenuated PAI-1 expression in neointimal regions and inhibited neointimal hyperplasia after balloon injury. Cilostazol inhibited PAI-1 expression by multiple mechanisms including downregulation of TGF-beta, JNK and p38 signaling pathways. Cilostazol also inhibited transactivating activity at the PAI-1 promoter by Smad3, leading to a suppression of PAI-1 gene transcription. Taken together with its antiproliferative effect on VSMCs, this may explain how cilostazol exerts its antithrombogenic effects after angioplasty and stent implantation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angioplasty, Balloon / adverse effects
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Angiotensin II / metabolism*
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Animals
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Binding Sites
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Blood Glucose / metabolism*
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Carotid Arteries / drug effects
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Carotid Arteries / metabolism
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Carotid Artery Injuries / drug therapy*
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Carotid Artery Injuries / etiology
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Carotid Artery Injuries / metabolism
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Carotid Artery Injuries / pathology
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Cell Proliferation / drug effects
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Cells, Cultured
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Cilostazol
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / pathology
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Dose-Response Relationship, Drug
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Fibrinolytic Agents / pharmacology*
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Hyperplasia
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology
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Phosphodiesterase Inhibitors / pharmacology
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Plasminogen Activator Inhibitor 1 / genetics
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Plasminogen Activator Inhibitor 1 / metabolism*
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Promoter Regions, Genetic / drug effects
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Smad3 Protein / metabolism
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Tetrazoles / pharmacology*
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Transcriptional Activation / drug effects
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Transforming Growth Factor beta / metabolism
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Tunica Intima / drug effects*
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Tunica Intima / metabolism
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Tunica Intima / pathology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Blood Glucose
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Fibrinolytic Agents
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Phosphodiesterase Inhibitors
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Plasminogen Activator Inhibitor 1
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Smad3 Protein
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Smad3 protein, rat
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Tetrazoles
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Transforming Growth Factor beta
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Angiotensin II
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Cilostazol