Cilostazol Suppression of High Glucose-Induced Vascular Smooth Muscle Cell Dysfunction - Role of RAGE Signaling

• Main Authors: Hsin-Yi Wang, 王欣羿
• Other Authors: Yi-Shing Shien
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/36453295818699836631

碩士 === 國防醫學院 === 微生物及免疫學研究所 === 101 === The prevalence of type 2 diabetes is rising at an alarming rate worldwide and a leading cause of morbidity and mortality associated with accelerated atherosclerosis, including coronary artery, cerebrovascular and peripheral arterial obstruction disease (PAOD). An emerging body of evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contribute to atherosclerosis and its complications. The receptor for advanced glycation end-products (RAGE) has been subsequently characterized as a multiligand receptor of the immunoglobulin superfamily of cell surface receptors. Driven by sustained HG and oxidative stress, enhanced AGEs generation coupled with RAGE hyperactivity was revealed as a critical pathway involved in diabetic micro- and macrovascular complications. Cilostazol is known as a clinical medicine in treating diabetic PAOD by improving HG-induced vascular dysfunction. Our clinical data showed cilostazol treatment in type 2 diabetic patients not only improved PAOD but also associated with changes in serum soluble RAGE and endothelial markers. However, it is still remained unclear whether cilostazol improves the diabetes related atherosclerosis through the pathway of RAGE. In this study, we used human umbilical artery SMC (HUASMC) to investigate whether cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. First, our result revealed cilostazol decreased RAGE, VCAM-1 and ICAM-1 expression in HG cultured HUASMC and also improved proliferation, adhesion and migration of HUASMC. Second, the effects of cilostazol were mainly through inhibiting RAGE/ERK/NF-ƙB pathway and HG induced reactive oxygen species (ROS) production. We conclude that the data provide an additional mechanism underlying the anti-atherosclerotic effect of cilostazol by influencing RAGE signal and the downstream molecules. Meanwhile, these result let us gain a greater understanding of the effectiveness and mechanisms that cilostazol involved in improving the HG induced VSMC dysfunction.