Mulberry polyphenols ameliorate atherogenic migration and proliferation by degradation of K-Ras and downregulation of its signals in vascular smooth muscle cell

Abstract

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.

Exploration of the Shared Gene Signatures and Molecular Mechanisms Between Ischemic Stroke and Atherosclerosis

“…Previous Bioinformatics Analysis Shows Elevated KRAS in Ischemic Stroke, 46 and can promote atherosclerotic plaque formation. 47 The mechanism of KRAS in ischemic stroke and atherosclerosis is not clear. By constructing a miRNA regulatory network, we obtained four miRNAs known to be associated with both IS and AS: hsa-miR-330-5p, hsa-miR-143-3p, hsa-miR-16-5p, hsa-miR-152-3p, and all regulate KRAS, suggesting that KRAS may be the most critical gene acting in atherosclerosis and ischemic stroke, possibly through ErbB signaling pathway, Choline metabolism in cancer, Neurotrophin signaling pathway, Thyroid hormone signaling pathway, FoxO signaling pathway, Insulin signaling pathway, Proteoglycans in cancer, MAPK signaling pathway.…”