- 作者: Sheng-Chiang Su, Yi-Jen Hung, Chia-Luen Huang, Yi-Shing Shieh, Chu-Yen Chien, Chi-Fu Chiang, Jhih-Syuan Liu, Chieh-Hua Lu, Chang-Hsun Hsieh, Chien-Ming Lin and Chien-Hsing Lee
- 作者服務機構: 1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 3. Division of Biochemistry, National Defense Medical Center, Taipei, Taiwan 4. School of Dentistry, National Defense Medical Center, Taipei, Taiwan 5. Department of Oral Diagnosis and Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 6. Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan 7. Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- 中文摘要:
- 英文摘要:
Background
Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction.
Objectives
In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism.
Method
We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected.
Results
Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture.
Conclusions
Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways. - 中文關鍵字:
- 英文關鍵字: Cilostazol, Vascular smooth muscle, RAGE, Diabetes