1. Division of Cardiovascular Surgery, Surgical Department, Chung Shan Medical University Hospital, Taichung 402, Taiwan
2. Department of Surgery, School of Medicine, Chung-Shan Medical University, Taichung 402, Taiwan
3. School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
4. Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
5. Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, 402, Taiwan
6. Department of Health Diet and Industry Management, Chung Shan Medical University, Taichung 402, Taiwan
7. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, 402, Taiwan
8. Institute of Medicine, Chung Shan Medical University, Taichung, 402, Taiwan
9. Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
#These authors contributed equally as first authors.
Extra-proliferation and increased migration of vascular smooth cells con-tribute to the formation of atherosclerosis. Ras small G proteins play a critical role in the prolif-eration and migration of a wide range of cells. Mulberry, an economic fruit in Asia, exhibits anti-inflammation, anti-migration, and anti-oxidant properties. The mechanisms of action of mulberry extracts on K-Ras small G protein-induced proliferation and migration of vascular smooth muscle cell have not been extensively investigated. In this study, we explored the effects of mulberry polyphenol extracts (MPE) on the proliferation and migration of K-Ras-overexpressing A7r5 smooth muscle cells. The overexpression of K-Ras enhanced the ex-pression and activity of matrix metalloproteinase (MMP)-2, promoted vascular endothelial growth factor (VEGF) production, and eventually triggered the migration of A7r5 cells. Treatment with MPE attenuated K-Ras-induced phenomenon. In addition, MPE blocked K-Ras-induced actin fibril stress. MPE dose-dependently diminished K-Ras-induced Rho A, Rac1, CDC42, and phosphorylated focal adhesion kinase (FAK) expression. MPE elevated Rho B ex-pression. Phosphorylated AKT and glycogen synthase kinase (GSK) induced by K-Ras were also repressed by MPE treatment. MPE enhanced the interaction of IκB with NFκB. MPE restored the G0/G1 population and p21 and p27 expressions, which were repressed by K-Ras. Finally, MPE triggered the degradation of K-Ras by ubiquitination. MPE inhibited the migration and proliferation of vascular smooth cell through K-Ras-induced pathways and eventually pre-vented atherosclerosis.
Keywords: mulberry polyphenol extracts (MPE), vascular smooth muscle cells, migration, proliferation, K-Ras