title: Protein tyrosine phosphatase SHP-2 is positively involved in platelet-derived growth factor-signaling in vascular neointima formation via the reactive oxygen species-related pathway.
abstract: The roles of Src homology domain 2-containing protein tyrosine phosphatase 2 (SHP-2) and its signaling in atherosclerosis have not been explored. Therefore, we investigated the roles of SHP-2 in the movement of rat aortic smooth muscle cells (RASMCs) and in the neointima formation of the carotid artery. Platelet-derived growth factor (PDGF)-BB (1 - 20 ng/ml) increased the activity and phosphorylation of SHP-2 and migration in RASMCs and these were suppressed by SHP-2 inhibitor NSC-87877 (30 µM) and small interfering RNA of SHP-2. PDGF-BB increased the phosphorylations of spleen tyrosine kinase (Syk) and p38 mitogen-activated protein kinase (MAPK), which were recovered by inhibition of SHP-2. Moreover, PDGF-BB increased the levels of reactive oxygen species (ROS) and ROS inhibitors decreased PDGF-BB-increased migration. Treatment of RASMCs with H(2)O(2) (100 µM) increased cell migration and SHP-2 phosphorylation and also enhanced the phosphorylation levels of Syk and p38 MAPK. Oral administration of NSC-87877 (10 mg/kg) significantly suppressed neointima formation in a rat model of carotid artery injury. These results suggest that the activity of SHP-2 is controlled by ROS and is positively involved in the regulation of PDGF-BB-induced RASMC migration and neointima formation.
authors.affiliation: Institute of Functional Genomics, School of Medicine, Konkuk University, 322 Danwol-dong, Choongju 380-701, Korea.
authors.forename: Kyung-Jong
authors.initials: KJ
authors.lastname: Won
authors.forename: Hwan Myung
authors.initials: HM
authors.lastname: Lee
authors.forename: Chang-Kwon
authors.initials: CK
authors.lastname: Lee
authors.forename: Hai Yue
authors.initials: HY
authors.lastname: Lin
authors.forename: Haerang
authors.initials: H
authors.lastname: Na
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lim
authors.forename: Hui Yul
authors.initials: HY
authors.lastname: Roh
authors.forename: Seobo
authors.initials: S
authors.lastname: Sim
authors.forename: Hyuk
authors.initials: H
authors.lastname: Song
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D058426:Neointima / Q000503:physiopathology*; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016877:Oxidants; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D017382:Reactive Oxygen Species; D000077214:Becaplermin; D006861:Hydrogen Peroxide; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11