title: Cilostazol inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor expression in artery wall and neointimal region after vascular injury.
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.
authors: Department of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors: Kyeong-Min
authors: KM
authors: Lee
authors: Hyo-Jeong
authors: HJ
authors: Lee
authors: Mi-Kyung
authors: MK
authors: Kim
authors: Hye-Soon
authors: HS
authors: Kim
authors: Gwon-Soo
authors: GS
authors: Jung
authors: Seung-Ho
authors: SH
authors: Hur
authors: Hyoung Tae
authors: HT
authors: Kim
authors: Won-Hyun
authors: WH
authors: Cho
authors: Jung-Guk
authors: JG
authors: Kim
authors: Bo-Wan
authors: BW
authors: Kim
authors: Jeong Ok
authors: JO
authors: Lim
authors: Hueng-Sik
authors: HS
authors: Choi
authors: Ki-Up
authors: KU
authors: Lee
authors: Keun-Gyu
authors: KG
authors: Park
authors: In-Kyu
authors: IK
authors: Lee
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001786:Blood Glucose / Q000378:metabolism*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000077407:Cilostazol; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006965:Hyperplasia; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077407:Cilostazol