Korean Diabetes Journal 2001;25(6):446-459.
Published online December 1, 2001.
The Effect of alpha-Lipoic Acid on Vascular Smooth Muscle Cell Proliferation, Migration, Neointimal Formation and PAI-1 Expression.
Dong Woo Shin, Dong Wook Lee, Sang Jun Lee, Hye Soon Kim, Hyo Gyoung Kang, Jong Deok Ahn, In Kyu Lee
1Department of Internal Medicine, Keimyung University Dongsan Medical Center, Korea.
2Institute for Medical Science, Keimyung University Dongsan Medical Center, Korea.
Abstract
BACKGROUND
Exposure to large amounts of glucose causes a characteristic dysfunction and morphologic changes of the endothelium by an increased production of reactive oxygen species (ROS) in diabetes. The plasminogen activator inhibitor-1 (PAI-1), which modulates fibrinolysis and cell migration, may influence proteolysis and neointimal formation in vascular smooth muscle cells (VSMC). Antioxidants have been proposed to inhibit multiple proatherogenic events. This study investigated the effect of (alpha)-Lipoic acid on PAI-1 expression and VSMC proliferation and migration both in vivo and in vitro. METHODS: In the in vitro study, cultured rat aortic smooth muscle cells (RASMC) were incubated in a medium containing high glucose (22 mM) and 100 nM angiotensin II for 4 hour. After (alpha)-Lipoic acidtreatment, a -migration and growth assay of the RASMC, and a gel mobility shift assay and reporter gene analysis for nuclear factor- B (NF-kappa B) and northern blot analysis for PAI-1 were performed. In the in vivo study, the effect of (alpha)-Lipoic acid on neointimal hyperplasia in a rat carotid balloon injury model was evaluated. RESULTS: RASMC migration was inhibited significantly by (alpha)-Lipoic acid (p<0.01), but their proliferation was not inhibited. The NF-kappa B DNA binding activity and NF-kappa B promoter activity was inhibited by (alpha)-Lipoic acid significantly (p<0.01). (alpha)-Lipoic acid inhibited PAI-1 mRNA expression by high glucose and angiotensin II in dose dependent manner (p<0.05). In the rat carotid artery balloon injury model, neointimal formation was reduced by (alpha)-Lipoic acid treatment in a dose dependent manner significantly (p<0.01). CONCLUSION: (alpha)-Lipoic acid suppresses migration, but not proliferation in RASMC. (alpha)-Lipoic acid also reduce neointima formation in a rat carotid balloon injured model. This effect might be related to the blocking of NF-kappa B which increase the expression of the genes associated with atherosclerosis including TNF-alpha, IL-1, IL-6, endothelin-1, MCP-1, VCAM-1, ICAM-1, E-selectin, tissue factor.
Key Words: Rat aortic smooth muscle cell, Neointimal hyperplasia, Oxidative stress, Nuclear factor-kappa B, (alpha)-Lipoic acid


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