Cilostazol inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor expression in artery wall and neointimal region after vascular injury.
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.
Lee
Kyeong-Min
KM
Department of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Lee
Hyo-Jeong
HJ
Kim
Mi-Kyung
MK
Kim
Hye-Soon
HS
Jung
Gwon-Soo
GS
Hur
Seung-Ho
SH
Kim
Hyoung Tae
HT
Cho
Won-Hyun
WH
Kim
Jung-Guk
JG
Kim
Bo-Wan
BW
Lim
Jeong Ok
JO
Choi
Hueng-Sik
HS
Lee
Ki-Up
KU
Park
Keun-Gyu
KG
Lee
In-Kyu
IK
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
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