Department of Internal Medicine and Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Atherosclerosis. 2009 Dec;207(2):391-8. doi: 10.1016/j.atherosclerosis.2009.06.016. Epub 2009 Jun 18.
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.
纤溶酶原激活物抑制剂-1（PAI-1）在血管组织中的表达增加是将糖尿病与经皮冠状动脉介入治疗后的再狭窄联系起来的一个潜在因素。最近的研究表明，西洛他唑，一种选择性的 3 型磷酸二酯酶抑制剂，可预防糖尿病患者经冠状动脉成形术和支架植入术后的新生内膜过度增生和支架内血栓形成。然而，这种药物的分子机制尚未完全阐明。我们研究了西洛他唑是否抑制血管平滑肌细胞（VSMCs）和新生内膜过度增生中的 PAI-1 表达。我们发现，西洛他唑可有效抑制血管紧张素 II、高糖和 TGF-β在体内和体外刺激的 PAI-1 表达。西洛他唑可减轻球囊损伤后新生内膜区域的 PAI-1 表达并抑制新生内膜过度增生。西洛他唑通过多种机制抑制 PAI-1 表达，包括下调 TGF-β、JNK 和 p38 信号通路。西洛他唑还抑制 Smad3 对 PAI-1 启动子的转录激活活性，从而抑制 PAI-1 基因转录。加上其对 VSMCs 的抗增殖作用，这可能解释了西洛他唑在经皮冠状动脉成形术和支架植入术后如何发挥其抗血栓形成作用。
