title: Protein tyrosine phosphatase PTPepsilonM negatively regulates PDGF beta-receptor signaling induced by high glucose and PDGF in vascular smooth muscle cells.
abstract: Vascular smooth muscle cell (VSMC) proliferation and migration and vascular endothelial cell (VEC) dysfunction are closely associated with the development of atherosclerosis. We previously demonstrated that protein tyrosine phosphatase ε M (PTPεM) promotes VEC survival and migration. The present study investigates the biological functions of PTPεM in VSMCs and determines whether PTPεM is implicated in diabetes-accelerated atherosclerosis. We overexpressed wild-type and inactive PTPεM and an small interfering RNA (siRNA) of PTPεM by using an adenovirus vector to investigate the effects of PTPεM upon platelet-derived growth factor (PDGF)- and high glucose (HG)-induced responses of rat VSMCs in vitro. We found that PTPεM decreased PDGF-induced DNA synthesis and migration by reducing the phosphorylation level of the PDGF β-receptor (PDGFRβ) with subsequently suppressed H(2)O(2) generation. The HG content in the medium generated H(2)O(2), upregulated PDGFRβ expression and its tyrosine-phosphorylation, and elevated NADPH oxidase 1 (Nox1) expression even without exogenous PDGF, all of which were downregulated by PTPεM. The PDGFR inhibitor AG1296 also blocked HG-induced Nox1 expression and H(2)O(2) production. Moreover, HG suppressed PTPεM expression itself, which was blocked by the antioxidant N-acetyl-l-cysteine. The effects of PTPεM siRNA were the opposite of those of wild-type PTPεM. Therefore, PTPεM negatively regulates PDGFRβ-mediated signaling pathways that are crucial for the pathogenesis of atherosclerosis, and PTPεM may be involved in diabetes-accelerated atherosclerosis.
authors.affiliation: Graduate School of Life and Environmental Sciences, Alliance for Research on North Africa, University of Tsukuba, Ibaraki, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Shimizu
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Chie
authors.initials: C
authors.lastname: Murakami
authors.forename: Naohito
authors.initials: N
authors.lastname: Aoki
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyazaki
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D004247:DNA / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D004247:DNA; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; D020797:Receptor, Platelet-Derived Growth Factor beta; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D005947:Glucose; D000111:Acetylcysteine