title: Methyl Protodioscin, a Steroidal Saponin, Inhibits Neointima Formation in Vitro and in Vivo.
abstract: Restenosis (or neointimal hyperplasia) remains a clinical limitation of percutaneous coronary angioplasty. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are known to be involved in the development of restenosis. The present study aimed to investigate the ability and molecular mechanisms of methyl protodioscin (1), a steroidal saponin isolated from the root of Dioscorea nipponica, to inhibit neointimal formation. Our study demonstrated that 1 markedly inhibited the growth and migration of VSMCs (A7r5 cells). A cytometric analysis suggested that 1 induced growth inhibition by arresting VSMCs at the G1 phase of the cell cycle. A rat carotid artery balloon injury model indicated that neointima formation of the balloon-injured vessel was markedly reduced after extravascular administration of 1. Compound 1 decreased the expression levels of ADAM15 (a disintegrin and metalloprotease 15) and its downstream signaling pathways in the VSMCs. Moreover, the expressions and activities of matrix metalloproteinases (MMP-2 and MMP-9) were also suppressed by 1 in a concentration-dependent manner. Additionally, the molecular mechanisms appear to be mediated, in part, through the downregulation of ADAM15, FAK, ERK, and PI3K/Akt.
authors.affiliation: School of Pharmacy, China Medical University , Taichung 40402, Taiwan.
authors.forename: Yun-Lung
authors.initials: YL
authors.lastname: Chung
authors.affiliation: Department of Pharmacy, Taipei Medical University , Taipei 11031, Taiwan.
authors.forename: Chun-Hsu
authors.initials: CH
authors.lastname: Pan
authors.affiliation: Department of Biomedical Informatics, Asia University , Taichung 41354, Taiwan.
authors.forename: Charles C-N
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Cancer Biology and Drug Dsicovery, Taipei Medical University , Taipei 11031, Taiwan.
authors.forename: Kai-Cheng
authors.initials: KC
authors.lastname: Hsu
authors.affiliation: School of Pharmacy, China Medical University , Taichung 40402, Taiwan.
authors.forename: Ming-Jyh
authors.initials: MJ
authors.lastname: Sheu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University , Xiamen 361005, China.
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
authors.affiliation: School of Pharmacy, China Medical University , Taichung 40402, Taiwan.|Department of Pharmacy, Taipei Medical University , Taipei 11031, Taiwan.
authors.forename: Chieh-Hsi
authors.initials: CH
authors.lastname: Wu
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000465:Algorithms; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D020212:Carotid Artery Injuries; D002465:Cell Movement; D049109:Cell Proliferation; D027742:Dioscorea / Q000737:chemistry*; D004144:Diosgenin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006965:Hyperplasia / Q000188:drug therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008962:Models, Theoretical; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D058426:Neointima / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018517:Plant Roots / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D004365:Drugs, Chinese Herbal; D008565:Membrane Proteins; D012503:Saponins; C425324:methyl protodioscin; D019869:Phosphatidylinositol 3-Kinases; D051722:ADAM Proteins; C098660:ADAM15 protein, human; D004144:Diosgenin