title: Anti-atherogenic activity of wild grape (Vitis thunbergii) extract antagonizing             smooth muscle cell proliferation and migration promoted by neighboring macrophages.
abstract: The proliferation and migration of vascular smooth muscle cells (SMCs) play critical roles in intimal thickening and neointimal hyperplasia in early-phase atherosclerosis. This study tested whether wild grape extract (WGE) suppressed the proliferation and migration of human aortic SMCs induced by neighboring macrophages. Cellular expression of fibrogenic connective tissue growth factor (CTGF) and secretion of collagen IV and matrix metalloproteinase (MMP)-2 were determined in SMCs exposed to THP-1-differentiated macrophage-conditioned media. Proliferation was enhanced in SMCs exposed to macrophage-conditioned media collected during the early stage of differentiation, which was attenuated by treatment with ≥ 10 µg/ml WGE. Increased secretion of CTGF and collagen IV macrophage-conditioned media was suppressed in WGE-supplemented SMCs. TGF-β1-promoted production of CTGF and collagen IV was suppressed by blocking TGF-β receptors of R1 and R2 in SMCs. WGE repressed macrophage-conditioned media-upregulated MMP-2 secretion, indicating that WGE had an ability to encumber plaque rupture within atherosclerotic lesions. In addition, ≥ 1 µg/ml WGE ameliorated the migration of SMCs promoted by neighboring macrophages. These results demonstrate that WGE retarded neointimal hyperplasia and thickening within atherosclerotic plaques largely comprising of macrophages and SMCs. Therefore, WGE may be developed as an anti-proliferative and anti-migratory agent targeting SMCs in the proximity of newly differentiated and resident macrophages.
authors.affiliation: Department of Food and Nutrition, Hallym University, Chuncheon,                     Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D027843:Vitis / Q000737:chemistry*
chemical_list: D024141:Collagen Type IV; D017077:Culture Media, Conditioned; D010936:Plant Extracts; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14